Pathogen recognition is central to the induction of T cell differentiation. Groups of pathogens share similar structures known as pathogen-associated molecular patterns (PAMPs), which are recognised by pattern recognition receptors (PRRs) expressed on dendritic cells (DCs) to induce cytokine expression. PRRs include archetypical Toll-like receptors (TLRs) and non-TLRs such as retinoic acid-inducible gene I (RIG-I)-like receptors, C-type lectin receptors (CLRs) and intracellular nucleotide-binding domain and leucine-rich-repeat-containing family (NLRs). PRR recognition of PAMPs can lead to the activation of intracellular signalling pathways that elicit innate responses against pathogens and direct the development of adaptive immunity. CLRs comprises a large family of receptors which bind carbohydrates, through one or more carbohydrate recognition domains (CRDs), or which possess structurally similar C-type lectin-like domains (CTLDs) which do not necessarily recognise carbohydrate ligands. Some CLRs can induce signalling pathways that directly activate nuclear factor-kB (NF-kB), whereas other CLRs affect signalling by Toll-like receptors. These signalling pathways trigger cellular responses, including phagocytosis, DC maturation, chemotaxis, the respiratory burst, inflammasome activation, and cytokine production.
View original pathway at Reactome.
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Co-immunoprecipitation studies and size exclusion chromatography analysis indicate that the high molecular weight (around 700 to 900 kDa) IKK complex is composed of two kinase subunits (IKK1/CHUK/IKBKA and/or IKK2/IKBKB/IKKB) bound to a regulatory gamma subunit (IKBKG/NEMO) (Rothwarf DMet al. 1998; Krappmann D et al. 2000; Miller BS & Zandi E 2001). Variants of the IKK complex containing IKBKA or IKBKB homodimers associated with NEMO may also exist. Crystallographic and quantitative analyses of the binding interactions between N-terminal NEMO and C-terminal IKBKB fragments showed that IKBKB dimers would interact with NEMO dimers resulting in 2:2 stoichiometry (Rushe M et al. 2008). Chemical cross-linking and equilibrium sedimentation analyses of IKBKG (NEMO) suggest a tetrameric oligomerization (dimers of dimers) (Tegethoff S et al. 2003). The tetrameric NEMO could sequester four kinase molecules, yielding an 2xIKBKA:2xIKBKB:4xNEMO stoichiometry (Tegethoff S et al. 2003). The above data suggest that the core IKK complex consists of an IKBKA:IKBKB heterodimer associated with an IKBKG dimer or higher oligomeric assemblies. However, the exact stoichiometry of the IKK complex remains unclear.
The IP3 receptor (IP3R) is an IP3-gated calcium channel. It is a large, homotetrameric protein, similar to other calcium channel proteins such as ryanodine. The four subunits form a 'four-leafed clover' structure arranged around the central calcium channel. Binding of ligands such as IP3 results in conformational changes in the receptor's structure that leads to channel opening.
During the phosphorylation of the IKK beta, the regulatory subunit NEMO undergoes K-63-linked polyubiquitination. Ubiquitinated TRAF6 trimer, acts as a E3 ligase and induces this ubiquitination. The ubiquitin target sites in NEMO are not yet clearly identified. Studies of different NF-kB signaling pathways revealed several potential ubiquitination sites on NEMO (e.g., K285, K277, K309 and K399) (Fuminori et al. 2009).
NF-kB is sequestered in the cytosol of unstimulated cells through the interactions with a class of inhibitor proteins, called IkBs, which mask the nuclear localization signal (NLS) of NF-kB and prevent its nuclear translocation. A key event in NF-kB activation involves phosphorylation of IkB (at sites equivalent to Ser32 and Ser36 of IkB-alpha or Ser19 and Ser22 of IkB-beta) by IKK. The phosphorylated IkB-alpha is recognized by the E3 ligase complex and targeted for ubiquitin-mediated proteasomal degradation, releasing the NF-kB dimer p50/p65 into the nucleus to turn on target genes. (Karin & Ben-Neriah 2000)
Nuclear factor of activated T-cells (NFAT) is a transcription factor which induces genes responsible for cytokine production, for cell-cell interactions etc. NFAT transcription activity is modulated by calcium and Calcineurin concentration. In resting cells NFAT is phosphorylated and resides in the cytoplasm. Phosphorylation sites are located in NFAT's regulatory domain in three different serine rich motifs, termed SRR1, SP2 and SP. Upon stimulation, these serine residues are dephosphorylated by calcineurin, that thought to cause exposure of nuclear localization signal sequences triggering translocation of the dephosphorylated NFAT-CaN complex to the nucleus. Among all the phosphorylation sites one of the site in SRR-2 motif is not susceptable to dephosphorylation by CaN (Takeuchi et al. 2007, Hogan et al. 2003).
Calcineurin (CaN), also called protein phosphatase 2B (PP2B), is a calcium/Calmodulin (CaM)-dependent serine/threonine protein phosphatase. It exists as a heterodimer consisting of CaM-binding catalytic subunit CaN A chain and a Ca+2 binding regulatory CaN B chain. At low calcium concentrations, CaN exists in an inactive state, where the autoinhibitory domain (AID) binds to the active-site cleft. Upon an increase in calcium concentration CaM binds to Ca+2 ions and gets activated. Active CaM binds to CaN regulatory domain (RD) and this causes release of the AID and activation of the phosphatase (Rumi-Masante et al. 2012). Binding of calcium to CaN B regulatory chain also causes a conformational change of the RD of CaN A chain (Yang & Klee 2000).
The released NF-kB transcription factor (p50/p65) with unmasked nuclear localization signal (NLS) moves in to the nucleus. Once in the nucleus, NF-kB binds DNA and regulate the expression of genes encoding cytokines, cytokine receptors, and apoptotic regulators.
NFKB2 (also known as p100) is a member of the NF-kB family of transcription factors. It is synthesised as large precursor with an N-terminal RHD (Rel homology domain) and a C-terminal series of ankyrin repeats that masks the nuclear localization signal of NFKB2/p100 localising it to the cytosol. In resting cells, p100 is associated with RELB (Transcription factor RelB) in the cytosol. Upon cell stimulation, the IkB-like C terminus of p100 is proteolyzed, resulting in RELB-p52 dimers that translocate to the nucleus (Senftleben et al. 2001, Hayden & Ghosh 2004). IKKA (I kappa-B kinase alpha) does not associate directly with p100 but in the presence of NIK (NF-kB-inducing kinase), IKKA stably binds to p100. Serine residues 866 and 870 of p100 are essential for the recruitment of IKKA to p100 by NIK. This interaction is required for p100 phosphorylation and subsequent processing by IKKA (Xiao et al. 2001, 2004).
The catalytic activity of NF-kB-inducing kinase (NIK) is regulated by structural conformation rather than by phosphorylation events. Under normal conditions NIK may be present in an autoinhibited state in which its constitutively active kinase domain is shielded by the N-terminal inhibitory element and upon receptor induction NIK kinase domain adopts an active conformation, in agreement with its catalytic activity. This catalytically competent conformation is maintained by an N-terminal extension prior to the kinase domain rather than through a phosphorylation event (Liu et al. 2012). NIK, also known as MAP3K14 (MAPK kinase kinase 14), is a serine/threonine kinase in the MAP3K family (Malinin et al. 1997). In unstimulated cells NIK associates with a complex composed of TNF receptor-associated factor 2 (TRAF2), TRAF3 and cellular inhibitor of apoptosis 1 (cIAP1) and cIAP2. This molecular interaction with TRAF-cIAP complex appears to target NIK for ubiquitination and proteasomal degradation. In response to receptor stimulation, TRAF2 or TRAF3, or both are targeted for proteasomal degradation by cIAP-mediated ubiquitination, which triggers the release and stabilization of NIK (Razani et al. 2010).
Accumulated NF-kB-inducing kinase (NIK) activates I kappa-B kinase alpha (IKKA) by directly phosphorylating the Ser176 and Ser180 with in the activation loop of IKKA. This phoshorylation is required for IKKA activity (Ling et al. 1998). Besides activating IKKA, NIK also serves as a docking molecule recruiting IKKA to p100 (Xiao et al. 2004).
Phosphorylated C-terminal serines 866, 870 and 872 in NFKB2 creates binding site for beta-TRCP (beta-transducin repeat-containing protein), the receptor subunit of a SCF-type of E3 ubiquitin ligase, SCF beta-TRCP (Liang et al. 2006). The SKP1-CUL1-F-box (SCF) ubiquitin E3 ligase superfamily is the largest family of cullin-RING ligases, with interchangeable F-box proteins orchestrating the trafficking proteins for ubiquitination and degradation (Weathington & Mallampalli 2013). Beta-TRCP is an F-box protein that contains two domains, an F-box motif that binds SKP1 and allows assembly into SKP1-CUL1 complexes and a second protein-protein interaction domain that interacts with phosphorylated serines in NFKB2 (Bai et al. 1996, Skowyra et al. 1997, Patton et al. 1998).
Following ubiquitination Ikappa B-alpha (IKBA) is rapidly degraded by 26S-proteasome, allowing NF-kB to translocate into the nucleus where it activates gene transcription (Spencer et al. 1999).
Ubiquitination of p100 is very specific. Lysine residue K855 has been identified as the anchoring site for ubiquitin and required for signaling mediated processing of p100 to p52. In the presence of SCF-beta-TRCP E3 ligase the ubiquitin (Ub) conjugated to E2 (E2-Ub thioester) is attached to p100 at K855 (Amir et al. 2004). Several rounds of ubiquitin conjugation can produce long chains of ubiquitin moieties (polyubiquitylation), the first of which is covalently bound to p100. At this point the polyubiquitylated p100 is committed to association with, and unfolding and processing by, the 26S proteasome (Pickart & Cohen 2004). Efficient ubiquitination of phosphorylated p100 by SCF-beta-TRCP E3 ligase also requires the presence of the components of the NEDD8 pathway: UBA3 (NEDD8-activating enzyme E1 catalytic subunit), UBC12 (NEDD8-conjugating enzyme Ubc12 (E2)), NEDD8 (Neural precursor cell expressed developmentally down-regulated protein 8). NEDD8 binds and promotes a conformational change in CUL1 that may result in efficient formation of an E2-E3 complex, thus stimulating SCF complexes activity (Kawakami et al. 2001, Morimoto et al. 2000, Read et al. 2000).
After being recruited into the NIK (NFkB-inducing kinase) complex, activated IKKA (I kappaB kinase alpha) phosphorylates serine residues 99, 108, 115, 123, 866, 870 and 872 located in both N- and C-terminal regions of NFKB2/p100. The phosphorylation of these specific serines is the prerequisite for ubiquitination and subsequent processing of p100. The C-terminal serine residues create a binding site for beta-TRCP (beta-transducinrepeat-containing protein), a ubiquitin E3 ligase (Xiao et al. 2001 & 2004, Liang et al. 2006).
Two major signaling steps are required for the removal of IkappaB (IkB) alpha an inhibitor of NF-kB: activation of the IkB kinase (IKK) and degradation of the phosphorylated IkB alpha. IKK activation and IkB degradation involve different ubiquitination modes; the former is mediated by K63-ubiquitination and the later by K48-ubiquitination. Mutational analysis of IkB alpha has indicated that K21 and K22 are the primary sites for addition of multiubiquitination chains while K38 and K47 are the secondary sites. In a transesterification reaction the ubiquitin is transferred from the ubiquitin-activating enzyme (E1) to an E2 ubiquitin-conjugating enzyme, which may, in turn, transfer the ubiquitin to an E3 ubiquitin protein ligase. UBE2D2 (UBC4) or UBE2D1 (UBCH5) or CDC34 (UBC3) acts as the E2 and SCF (SKP1-CUL1-F-box)-beta-TRCP complex acts as the E3 ubiquitin ligase (Strack et al. 2000, Wu et al. 2010). beta-TRCP (beta-transducin repeats-containing protein) is the substrate recognition subunit for the SCF-beta-TRCP E3 ubiquitin ligase. beta-TRCP binds specifically to phosphorylated IkB alpha and recruits it to the SCF complex, allowing the associated E2, such as UBC4 and or UBCH5 to ubiquitinate Ikappa B alpha (Baldi et al. 1996, Rodriguez et al. 1996, Scherer et al. 1995, Alkalay et al. 1995).
Once polyubiquitinated, the precursor p100 undergoes 26S proteasome mediated processing to form the mature p52 NF-kB subuunit. Different from complete degradation of other IkB proteins, the proteasome-mediated degradation of p100 only leads to loss of their C-terminal ankyrin repeat regions, leaving intact N-termini, p52 respectively (Amir et al. 2004).
TAK1-binding protein 1 (TAB1) is a TAK1-interacting protein and induces TAK1 (Transforming growth factor beta-associated kinase 1) kinase activity through promoting autophosphorylation of key serine/threonine sites of the kinase activation loop. There are four phosphorylation sites in the activation loop and analysis of these site mutants indicate that autophosphorylation of S192, is followed by sequential phosphorylation of T178, T187, and finally T184 (Scholz et al. 2010).
B-cell lymphoma/leukemia 10 (BCL10) is the downstream signaling partner of CARD9 and it interacts selectively with the CARD activation domain of CARD9. BCL10 functions as an adaptor between the effector IKK complex and the proximal signaling complexes that interact with CARD9 (Bertin et al. 2000).
Protein kinase C-delta (PRKCD), activated upon CLEC7A (Dectin-1)-SYK signaling, phosphorylates CARD9 leading to NF-kB activation (Strasser et al. 2012) and complex formation between CARD9 and BCL10. CLEC6A (Dectin-2) and CLEC4E (Mincle) also induces intracellular signaling through PRKCD and CARD9-BCL10-MALT1 pathway. Similar to the CLEC7A responses, both CLEC6A and CLEC4E-induced interleukin 10 (IL10) and tumour necrotic factor (TNF) production were severely impaired in the absence of PRKCD (Strasser et al. 2012). PRKCD is a member of the Ca2+ independent and diacylglycerol (DAG) dependent novel PKC subfamily. PKC family members exist in an immature inactive conformation that requires post-translational modifications to achieve catalytic maturity. The catalytic maturation of PRKCD involves the auto-phosphorylation of Ser645 and the phosphorylation of Thr507 and Ser664 (Li et al. 1997, Keranen et al. 1995). These phosphorylations of activation loop residues act as a priming step that allows the catalytic maturation of PRKCD (Dutil et al. 1998). Fully phosphorylated and primed PRKCD localises to the cytosol with its pseudosubstrate occupying the substrate-binding cavity. Signals that cause the lipid hydrolysis recruit PKC to membranes. The C1 domain in PRKCD is a cysteine-rich compact structure, identified as the interaction site for DAG and phorbol ester. PRKCD preferentially translocates to the plasma membrane (Stahelin et al. 2004, Newton 2010).
Following tyrosine phosphorylation, phospholipase C-gamma 2 (PLCG2) catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2 or PIP2] to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).
After binding BCL10, MALT1 also undergoes oligomerization. Like traditional caspases, MALT1 also becomes activated through the formation of oligomers. Once the CARD9-BCL10-MALT1 (CBM) signalosome is assembled, MALT1 functions as the effector protein and mediates activation of the IKK complex (McAllister-Lucas & Lucas 2008).
CARD interactions between CARD9 and BCL10 induce BCL10 oligomerization (through its CARD domain), required for oligomerization and activation of MALT1.
Spleen tyrosine kinase (SYK) is the key mediator of CLEC7A's (Dectin-1) downstream cellular responses, such as cytokine production and induction of the respiratory burst (Brown 2006). A phosphorylated tyrosine in CLEC7A provides the docking site for SYK. In contrast to usual ITAM receptors where dually phosphorylated tyrosines are necessary for SYK recruitment, phosphorylation of only the membrane proximal tyrosine is sufficient for SYK association with CLEC7A. Binding of SYK to the phosphorylated ITAM motif is sufficient to fully activate SYK (Tsang et al. 2008). SYK deficiency or SYK inhibitors inhibit CLEC7A-dependent cytokine production, MAPK activation and NF-kB activation, suggesting that SYK is essential for CLEC7A signalling (Rogers et al. 2005, Underhill et al. 2005, Fuller et al. 2007). Activation of NF-kB by SYK can be categorised into both canonical (c-Rel and p65) and NIK (NF-kB inhibitory kinase)-dependent non-canonical (RelB) routes (Gringhuis et al. 2009).
Activation of NF-kB signaling is a critical event downstream of CLEC7A (Dectin-1), CLEC6A (Dectin-2) (Bi et al. 2010) and CLEC4E (Mincle) (Yamasaki et al. 2008), requiring the adapter protein Caspase recruitment domain (CARD)-containing protein 9 (CARD9) in dendritic cells and in macrophages (Gross et al. 2006, Hara et al. 2007). CARD9 is analogous to CARD-containing MAGUK protein 1 (CARMA1), which mediates T-cell receptor (TCR) activation of NF-kB in lymphocytes. CARD9 is downstream of SYK and becomes phosphorylated by PRKCD (Protein kinase C-delta) phosphorylates CARD9 on Thr-231 (T231), which is required for the signal-induced association of CARD9 with B-cell lymphoma 10 (BCL10) and Mucosa-associated lymphoid tissue 1 (MALT1) and the subsequent recruitment of MAP3K transforming growth factor beta activated kinase 1 (TAK1), leading to activation of the NF-kB pathway (Strasser et al. 2012). A homozygous loss-of-function mutation in human CARD9 results in a premature termination codon (Gln295*). Patients with this mutation are highly susceptible to fungal infections (Glocker et al. 2009).
Following 26S-proteasomal processing, NFKB2 p52:RELB dimer is translocated from cytosol into the nucleus where it stimulates expression of target genes (Lin & Karin 2003). Dectin-1 induced RELB-p52 triggers the transcription of chemokines C-C motif chemokine 17 (CCL17) and CCL22 and repression of interleukin 12B (IL12B) transcription (Gringhuis et al. 2009).
In humans, the IkB kinase (IKK) complex serves as the master regulator for the activation of NF-kB by various stimuli. It contains two catalytic subunits, IKK alpha and IKK beta, and a regulatory subunit, IKKgamma/NEMO. The activation of IKK complex is dependent on the phosphorylation of IKK alpha/beta at its activation loop and the K63-linked ubiquitination of NEMO. This basic trimolecular complex is referred to as the IKK complex. IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on S177 and S181 (S176 and S180 in IKK alpha) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.
Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is the main downstream target of BCL10. MALT1 interacts directly with BCL10 and this interaction involves a short stretch of amino acids that follow the BCL10 CARD motif (amino acids 107–119 of human BCL10) and the two immunoglobulin-like domains of MALT1 (Uren et al. 2000, Lucas et al. 2001).
Activation of SYK triggers multiple cascades, which induces NF-kB activation through a CARD9-dependent pathway. Phospholipase C-gamma 2 (PLCG2) is one of the key signaling components of the CLEC7A (Dectin-1) pathway that connects SYK activation to CARD9 recruitment. PLCG2 is activated upon CLEC7A engagement and triggers an intracellular Ca2+ flux. SYK and Src family kinases are upstream of PLCG2 (Xu et al. 2009, Tassi et al. 2009, Gorjestani et al. 2011). SYK phosphorylates PLCG2 on Y753 and Y759, enhancing the activity of PLCG2 (Suzuki-Inoue et al. 2004).
Membrane-bound PKC adopts an open conformation, in which the pseudosubstrate is released from the kinase domain, allowing downstream signaling (Newton 2010).
TRAF6 (tumor necrosis factor receptor-associated factor 6) is a RING (really interesting new gene) domain ubiquitin (Ub) ligase that mediates NF-kB activation by regulating the ubiquitination of transforming growth factor beta-activated kinase (TAK1) and IkB kinase (IKK). TRAF6 has been implicated as downstream effector of MALT1. MALT1 binds to TRAF6 through two putative C-terminal TRAF6-binding motifs (Sun et al. 2004). Gorjestani et al. demonstrate that TRAF6 and TAK1 are required for C-type lectin receptor-induced NF-kB activation and play critical roles in anti-fungal innate immune responses (Gorjestani et al. 2012).
The signalling abilities of CLEC7A (Dectin-1) depend on its cytoplasmic (immunoreceptor tyrosine based activation motif) ITAM-like motif. In contrast to traditional ITAM sequences which consists of dual YXXL sequences, CLEC7A's ITAM (hemi-ITAM) has only a single YXXL motif (Ariizumi et al. 2000). Despite its unusual ITAM, CLEC7A upon ligation with beta-glucan containing particles undergoes tyrosine phoshorylation by SRC kinases (Kerrigan & Brown 2010).
Activated CARD9 localised in lipid rafts may self-associate with other CARD9 molecules (oligomerization). Residues 140-420 of CARD9 contain heptad repeats characteristic of coiled-coil structures that function in protein oligomerization (Bertin et al. 2000).
Tyrosine-phosphorylated Phospholipase C-gamma 2 (PLCG2) translocates from the cytosol to the plasma membrane. At the membrane PLCG2 is in close proximity to phosphatidylinositol 4,5-bisphosphate (PIP2) and its other substrates generating the second messengers IP3 and DAG (Rhee 2001). This leads to the activation of CARD9-BCL10-MALT1/NF-kB signaling and stimulates calcineurin/NFAT signaling.
TRAF6 possesses ubiquitin ligase activity and undergoes K-63-linked auto-ubiquitination after its oligomerization. In the first step, ubiquitin is activated by an E1 ubiquitin activating enzyme. The activated ubiquitin is transferred to a E2 conjugating enzyme (a heterodimer of proteins Ubc13 and Uev1A also known as TRIKA1 (TRAF6-regulated IKK activator 1)) forming the E2-Ub thioester. Finally, in the presence of ubiquitin-protein ligase E3 (TRAF6, a RING-domain E3), ubiquitin is attached to the target protein (TRAF6 on residue Lysine 124) through an isopeptide bond between the C-terminus of ubiquitin and the epsilon-amino group of a lysine residue in the target protein (Deng et al. 2000, Lamothe et al. 2007). In contrast to K-48-linked ubiquitination that leads to the proteosomal degradation of the target protein, K-63-linked polyubiquitin chains act as a scaffold to assemble protein kinase complexes and mediate their activation through proteosome-independent mechanisms. This K63 polyubiquitinated TRAF6 activates the TAK1 kinase complex.
TAK1-binding protein 2 (TAB2), or its homologue TAB3, binds preferentially to K63-linked polyubiquitin chains in TRAF6 and links TRAF6 (TNF receptor-associated factor 6) to TAK1 (Transforming growth factor beta-associated kinase 1). TRAF6 ubiquitinates TAK1 on K34 and K158 and this triggers conformational changes in TAK1 that lead to autophosphorylation and activation (Fan et al. 2010, Hamidi et al. 2011).
CLEC7A (Dectin-1) was identified as a primary receptor for beta-glucans from fungi, bacteria, and plants and specifically recognises beta 1-3 linked glucans. Human CLEC7A has eight alternatively splice products of which only two are functional for beta-glucan binding (isoforms A and B) (Willment et al. 2001). CLEC7A possesses an extracellular C-type lectin-like domain (CTLD) that is connected by a stalk region to a transmembrane domain and cytoplasmic tail, which contains an immunoreceptor tyrosine-based activation (ITAM)-like motif. Two highly conserved amino acids (222W 224H in Human; 221W, 223H in Mouse) within the CTLD which have been identified as essential for beta-glucan binding (Brown et al. 2007, Adachi et al. 2004). Through the recognition of beta-glucans, CLEC7A binds several fungal species such as Aspergillus, Candida, Coccidioides, Pencillium, Pneumocystis and Saccharimyces. Ferwerda et al. (2009) suggest that chronic mucocutaneous candidiasis may be caused by a genetic defect of CLEC7A. The mutation of nucleotide A-->C causes a change of amino acid 238 from tyrosine to a stop codon (Tyr238*), leading to the loss of the last nine amino acids of the carbohydrate-recognition domain (CRD). This mutated form of CLEC7A is poorly expressed and does not mediate beta-glucan binding, leading to defective production of cytokines after stimulation with beta-glucans or Candida albicans (Ferwerda et al. 2009).
K-63 linked polyubiquitin (pUb) chain on TRAF6 provides a scaffold to recruit downstream effector molecules to activate NF-kB. Transforming growth factor beta-associated kinase 1 (TAK1) is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family that is shown to be an essential intermediate that transmits the upstream signals from the receptor complex to the downstream MAPKs and to the NF-kB pathway (Broglie et al. 2009). As a member of the MAP3K family, TAK1 is unique in that its activity requires its binding proteins TAK1-binding protein 1 (TAB1), TAB2 and TAB3. TAB1 acts as the kinase subunit of the TAK1 complex, aiding in the autophosphorylation of TAK1, whereas TAB2 and its homologue TAB3, acts as an adaptor of TAK1 that facilitate the assembly of TAK1 complex to TRAF6 (Takaesu et al. 2000, Ishitani et al. 2003). This protein kinase complex containing the kinase subunit TAK1 and the regulatory subunits TAB1 and TAB2/TAB3 is also known as TRIKA2 (TRAF6-regulated IKK activator 2) (Adhikari et al. 2007).
Tyrosine-phosphorylated Phospholipase C-gamma 2 (PLCG2) translocates from the cytosol to the plasma membrane. At the membrane PLCG2 is in close proximity to phosphatidylinositol 4,5-bisphosphate (PIP2) and its other substrates generating the second messengers IP3 and DAG (Rhee 2001). This leads to the activation of CARD9-BCL10-MALT1/NF-kB signaling.
CLEC6A (C-type lectin domain family 6 member A/Dectin-2 (Dendritic cell-associated C-type lectin 2)) a C-type lectin expressed by dendritic cells (DCs) and activated macrophages has been shown to bind structures with high mannose content (McGreal et al. 2006). It is reported to recognise a variety of pathogens including Candida albicans, Saccharomyces cerevisiae, Mycobacterium tuberculosis, Paracoccidioides brasiliensis, Histoplasma capsulatum, Aspergillus fumigatus, non-encapsulated Cryptococcus neoformans, Microsporum audouinii, Trichophyton rubrum, Schistosoma mansoni and house dust mite allergens (Sato et al. 2006, Gorjestani et al. 2011, Ritter et al. 2010, McGreal et al. 2006, Kerscher et al. 2013). Like other members of the Dectin-2 family, cytoplasmic region of CLEC6A has no obvious signalling motif and it associates with transmembrane adapter FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) to transduce a CLEC6A/Dectin-2 signalling.
CLEC4D (Macrophage C-type lectin (MCL)) is a member of the C-type lectin that recognises mycobacterial trehalose-6,6'-dimycolate (TDM) or cord factor likely to arise from gene duplication of CLEC4E (also called Minicle). CLEC4D is constitutively expressed on myeloid cells. It couples with FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) and acts as an activating receptor (Miyake et al. 2013).
CLEC4E (also called Mincle or CLECSF9) is a C-type lectin receptor (CLR) expressed in activated macrophages and dendritic cells (DCs) in response to several inflammatory stimuli, including LPS, TNF, IL6, IFN-gamma and cellular stresses (Matsumoto et al. 1999). Like the other activating receptors in the Dectin-2 family, CLEC4E is coupled with the FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) to transduce intracellular signalling (Yamasaki et al. 2008). CLEC4E possesses a typical carbohydrate recognition domain (CRD) containing an EPN (Glu-Pro-Asn) motif which is capable of recognising several types of carbohydrates, particularly those containing alpha-mannose. CLEC4E can recognise fungal (Candida albicans and Malassezia), mycobacterial (trehalose-6,6?-dimycolate (TDM)) and necrotic cell ligands implicating this receptor in anti-microbial immunity and homeostasis (Schoenen et al. 2010, Yamasaki et al. 2009, Graham & Brown. 2009).
Ligation of CLEC6A (C-type lectin domain family 6 member A/Dectin-2) and CLEC4E (Mincle) with their appropriate ligands trigger the tyrosine phosphorylation of the immune receptor tyrosine-based activation motif (ITAM) in the cytoplasmic tail of FCER1G chain. Tyrosine Y65 and Y76 in the ITAM are phosphorylated and this phosphorylation is mediated by Src kinases Lyn and Fyn (Sato et al. 2006, Yamasaki et al. 2008, Quek et al. 1998).
Phospholipase C-gamma (PLCG) binds to phosphorylated Tyr-348 (Tyr-342 in mouse) and Tyr-352 (Tyr-346 in mouse) in SYK with its C-terminal SH2 domain (Law et al. 1996). PLCG2 functions downstream of CLEC6A/Dectin-2 and triggers cytokine production in response to the infection by Candida albicans. PLCG2 deficiency results in the defective production of NF-kB and significantly reduced production of reactive oxygen species (ROS) following infection (Gorjestani et al. 2011).
Activation of SYK triggers multiple cascades, which induces NF-kB activation through a CARD9-dependent pathway. Phospholipase C-gamma 2 (PLCG2) is one of the key signaling components of the CLEC4E (Mincle)/CLEC6A (Dectin-2) pathway that connects SYK activation to CARD9 recruitment. PLCG2 is activated upon CLEC4E (Mincle)/CLEC6A (Dectin-2) engagement and triggers an intracellular Ca2+ flux. SYK and Src family kinases are upstream of PLCG2. SYK phosphorylates PLCG2 on Y753 and Y759, enhancing the activity of PLCG2 (Gorjestani et al. 2011, Suzuki-Inoue et al. 2004).
SYK is a cytoplasmic tyrosine kinase related to ZAP70 that is expressed in all hematopoietic cells and coimmunoprecipitates with the gamma chain associated with FCGRIIIA in macrophages and with FCERI in mast cells. Tyrosine phosphorylation of the FCER1G ITAM recruits SYK and initiates a signaling cascade, leading to the activation of transcription factors such as NF-kB via CARD9-BCL10-MALT1 (Kerscher et al. 2013).
CLEC4A (C-type lectin domain family 4 member A/Dendritic cell immunoreceptor (DCIR)) is expressed by all CD14+ monocytes, CD15+ granulocytes, all dendrite cell (DC) subsets and B cells in peripheral blood. The extracellular domain of CLEC4A has an EPS motif which recognises carbohydrates but the definitive carbohydrate ligands have not been defined. However, it has been identified as an attachment factor for HIV on DCs and hepatitis C virus (HCV) glycoprotein E2 on plasmacytoid dendritic cells (pDCs) (Lambert et al. 2008, Florentin et al. 2012, Kerscher et al. 2013). Unlike the other Dectin-2 family members, CLEC4A has a long cytoplasmic tail with a classical immunoreceptor tyrosine based inhibitory signalling motif (ITIMs) (Flornes et al. 2004). CLEC4A with its ITIM motif mediates inhibitory signalling through activation of the phosphatases SHP1 and SHP2 (Kanazawa et al 2003, Meyer-Wentrup et al. 2009). Activation of CLEC4A on DCs or pDCs leads to inhibition of TLR8-mediated IL12 and TNF production, and TLR9-induced IFN-alpha production (Lambert et al. 2011, Meyer-Wentrup et al. 2008). In humans, polymorphisms of CLEC4A have been associated with susceptibility to rheumatoid arthritis (Lorentzen et al. 2007).
SYK can autophosphorylate and autophosphorylation increases its activity. It is more readily activated by autophosphorylation although it is rapidly activated by Src family kinases. SYK has multiple sites of phosphorylation which both regulate its activity and serve as docking sites for other proteins (Sada et al. 2001). Some of these sites include Y131 of interdomain A, Y323, Y348, and Y352 of interdomain B, and Y525 and Y526 within the activation loop of the kinase domain and Y630 in the C-terminus (Zhang et al. 2002, Lupher et al. 1998, Furlong et al. 1997).
CLEC4C (C-type lectin domain family 4 member C/Blood dendritic cell antigen 2 (BDCA2)) is a member of the Dectin-2 family expressed exclusively on plasmacytoid dendritic cells (pDCs). CLEC4C is capable of binding certain CD14+ monocytes, monocyte-derived DCs and several tumour cell lines by recognising sugars asialo-galactosyl-oligosaccharides with terminal beta1-4- and beta1-3-galactose residues. CLEC4C has also been shown to bind the HIV-1 envelope glycoprotein gp120 and hepatitis C virus (HCV) glycoprotein E2 (Kerscher et al. 2013, Riboldi et al. 2011, Florentin et al. 2011). CLEC4C lacks signalling motif in its cytoplasmic tail and associates with transmembrane adapter FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) to induce intracellular signal transduction in a B-cell receptor (BCR)-like fashion employing SYK to regulate the immune functions of pDCs. The FCERG-SYK signalling pathway interferes with TLR9-induced activation of pDC, inhibiting type I IFN secretion (Cao et al. 2007, Dzionek et al. 2001, Rock et al. 2007, Riboldi et al. 2011).
CD209 (DC-SIGN) acts as an adhesion molecule and besides foreign antigens (Ags), it binds to a number of endogenous ligands, particularly to intracellular adhesion molecule 2 (ICAM2) on endothelial cells. This CD209-ICAM2 interaction regulates chemokine-induced transmigration of dendritic cells across both resting and activated endothelium (Geijtenbeek et al. 2000).
Both CLEC7A (Dectin-1) and CD209 (DC-SIGN) modulates Toll-like receptor signalling by activating RAF1 which in turn induces the phosphorylation of p65 (RELA) subunit leading to the modification of p50/p65 NF-kB dimer (Gringhuis et al. 2007 & 2009). Gringhuis et al. demonstrated that CD209 (DC-SIGN) stimulated by ManLAM (lipoarabinomannan) activates the small GTPase RAS. Immunoblotting detected active RAS in dendritic cells when induced by ManLAM (Gringhuis et al. 2007). RAF1 is recruited to the membrane through an interaction with the active form of RAS.
CD209 (DC-SIGN) interacts with pathogens through either mannose or fucose containing glycans. It interacts with mannose capped cell-wall component of Mycobacterium tuberculosis ManLAM (lipoarabinomannan). The carbohydrate recognition domain (CRD) of CD209 recognizes Man-LAM and lipomannans and the amount of Man-LAM determines the binding strength. The interaction of ManLAM and CD209 leads to the activation of serine/threonine kinase RAF1 and increases the production of the immunosuppressive cytokine interleukin 6 (IL6), IL10 and IL12 in the presence of Toll like receptor stimulation (Geijtenbeek et al. 2003, Gringhuis et al. 2007 & 2009).
Contact between dendritic cells (DC) and resting T cells is essential to initiate a primary immune response. CD209 binds the intracellular adhesion molecule 3 (ICAM3) with very high affinity. CD209 interacts primarily with the immunoglobulin (Ig)-like second domain of ICAM2 and ICAM3. CD209-ICAM3 interaction mediates clustering of DCs with naive T cells forming a DC-T cell synapse (Geijtenbeek et al. 2000). CD209 binding to ICAM3 is calcium dependent, and CD209 CRD (carbohydrate recognition domain) binds two Ca2+ ions, one essential for tertiary structure and the other for coordinating ligand binding (Feinberg et al. 2001, Svajger et al. 2010).
Protein kinase A (PKA/PRKACA) and Ribosomal protein S6 kinase alpha-5 (RPS6KA5/MSK1/SAPK1) phosphorylate serine 276 (S276) in the Rel homology domain (RHD) of nuclear p65 subunit RELA (Yoon et al. 2008, Reber et al. 2009). Few other phosphorylation sites (S311, S529 and S536) have also been proposed in RELA (Duran et al. 2003) note: in this reaction we are showing only S276 phosphorylation)). Phosphorylation of RELA subunit enhances the association of RELA with p300 and this is a prerequisite for later NF-kB modification by histone acetyltransferases (HATs) p300/CBP. Phosphorylation of RELA also cross-regulates CLEC7A (dectin-1) mediated non-canonical NF-kB pathway by forming inactive p65 and RELB dimers, that cannot bind DNA.
Phosphorylation of tyrosine 340, 341 (Y340,341) on RAF1 in response to CD209 (DC-SIGN) signalling depends on yet unidentified members of the Src family of tyrosine kinases (SFKs). In imunoprecipitation studies, CD209 from lipid rafts of dendritic cells was found to co-precipitate with LYN, a member of the SFK, as well as with SYK tyrosine kinase, indicating their possible involvement in DC-SIGN signalling (Caparros et al. 2006, Svajger et al. 2010).
RAF regulation is highly complex and is not solely mediated by conformational changes but also requires phosphorylation. Several phosphorylation sites on RAF1 have been identified that are involved in its kinase activity. Two of these phosphorylation sites are serine 338 (S338) and tyrosine 340 and 341 (Y340/341). Gringhuis et al. demonstrated that ManLAM activation of CD209 (DC-SIGN) results in induced phosphorylation of RAF1 on S338 and Y340/341. The phosphorylation of S338 is mediated by p21-activated kinases (PAK). Inhibition of Rho GTPases with toxin B blocks CD209 induced phosphorylation of RAF1on S338 (Gringhuis et al. 2007, Wellbrock et al. 2004).
Upon CLEC7A (Dectin-1) and CD209 (DC-SIGN) activation, RAF1 translocates to the membrane through interaction with the active form of RAS. This interaction induces a conformational change in RAF1 and is required for RAF1 activation (Gringhuis et al. 2007, Wellbrock et al. 2004).
Acetylation of RELA/p65 subunit differentially regulates distinct biological activities of the NF-kB transcription factor complex. The acetylation enables increased DNA binding and transcriptional activity by NF-kB, leading to up-regulated IL6 (interleukin 6), IL10, IL12p35, IL12p40 and IL23p19 production (Geijtenbeek and Gringhuis 2009). Acetyltransferases p300 and CBP are involved in the acetylation of RELA on multiple sites including lysines 122, 123, 218, 221 and 310. Acetylation of lysine 221 by p300/CBP increases the DNA binding affinity of RELA for the IkB enhancer and, together with acetylation of lysine 218, impairs assembly of RELA with newly synthesized IkBalpha, which shuttles in and out of the nucleus. Acetylation of lysine 310 does not modulate DNA binding or IkBalpha assembly but markedly enhances the transcriptional activity of NF-kB (Chen et al. 2002, 2005).
ASC (adaptor protein apoptosis-associated speck-like protein containing a CARD) is a pro-apoptotic protein containing a pyrin domain (PD) and a caspase-recruitment domain (CARD). ASC with its PD domain physically interacts with caspase-8. Formation of the MALT1–caspase-8 complex is a prerequisite for the association of caspase-8 with ASC. ASC is necessary for the recruitment of pro-IL1B into the proximity of activated caspase-8 (Gringhuis et al. 2012).
Interleukin-1beta (IL1B) is secreted as inactive precursor, and the processing of pro-IL1B depends on cleavage by proteases. Active caspase-8 inflammasome is capable of cleaving the 31-kDa inactive IL1B precursor form into the bioactive 17-kDa IL1B.
After CLEC7A (dectin-1) triggering, MALT1 and caspase-8 associate to form BCL10-MALT1-Caspase-8 complex. MALT1 has a crucial dual role in the expression of IL1B by CLEC7A. It is involved in the transcription of IL1B by activating NF-kB and the other role in processing of pro-IL1B by mediating the formation and activation of a MALT1-caspase8-ASC (adaptor protein apoptosis-associated speck-like protein containing a CARD) complex (Gringhuis et al. 2012). The paracaspase domain of MALT1, in a protease-independent manner, induces caspase-8 activation through direct association (Kawadler et al. 2008).
The phosphorylation of p65 subunit has been shown to be important for RELA transcriptional activity. Once phosphorylated RELA/p65 has been shown to recruit transcriptional coactivators CREB binding protein (CBP) and p300 (Chen at al. 2002). The association between CBP/p300 and NF-kB p65 occurs through RHD (Rel homology domain) and C-terminal transactivation domain (Zong et al. 1998). Both p300 and CBP contain a histone acetyltransferase (HAT) enzymatic activity that regulates gene expression through acetylation of RELA, and promoter proximal nucleosomal histones, resulting in increased accessibility of the DNA for other essential regulators (Kalkhoven 2004).
Phosphorylated RELA besides undergoing further acetylation by the histone acetyltransferases (HATs) CBP and p300 also forms a complex with RELB to form inactive RELA-RELB dimers that cannot bind DNA. Because RELB requires p50 or p52 as a dimerization partner to bind DNA, it is possible that sequestration of RELB from its complex partners p50 and p52 by RELA might account for the lack of RELB DNA binding. RELA-RELB dimers have important regulatory consequences on dectin-1 mediated non-canonical NF-kB pathway. Inactive p65-RELB dimers blocks binding of RELB-p52 to the promoters of the chemokine genes CCL17 (CC-chemokine ligand 17) and CCL22, thereby blocking chemokine expression (Gringhuis et al. 2009).
Glycoproteins in human tumors often exhibit abnormal glycosylation patters, e.g. certain Lewis structures, TF antigen, Tn antigen and/or their sialylated forms, which creates additional binding sites for glycoreceptors. The C-type lectin domain family 10 member A (CLEC10A/MGL/CD301) is a calcium-type (C-type) lectin glycoreceptor expressed on dendritic cells (DCs) (Suzuki et al. 1996). It recognizes glycoproteins from both altered self and pathogens due to its monosaccharide specificity for galactose (Gal) and N-acetylgalactosamine (GalNAc). CLEC10A specifically binds glycans with terminal GalNAc residues such as Tn antigen (GalNAcalpha-serine/threonine), 6-sulfo-Tn, Lac-di-NAc (Galbeta1,4-GlcNAc) as well as core 5 (GalNAcalpha1-3GalNAcalpha-) and core 6 (GlcNAcbeta1-6GalNAcalpha-) that are expressed in human tumors (Mortezai et al. 2013, van Vliet et al. 2005). CLEC10A on immature human monocyte-derived DCs has been shown to recognize and internalize the three tandem repeat peptides of Mucin-1 carrying Tn (Tn-MUC1) (Denda-Nagai et al. 2010).
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DataNodes
NIK:p-176,S180-IKKA
dimer:p-7S-p100:SCF-beta-TRCPNIK:p-S176,180-IKKA
dimer:p-7S-p100:RELBNIK:p-S176,180-IKKA
dimer:p100:RELBNIK:p-S176,180-IKKA
dimerdimer:HIV gp120,HCV
gp E2oligomers:active
caspase-8:ASCbound to CBM
complexAnnotated Interactions
NIK:p-176,S180-IKKA
dimer:p-7S-p100:SCF-beta-TRCPNIK:p-176,S180-IKKA
dimer:p-7S-p100:SCF-beta-TRCPNIK:p-176,S180-IKKA
dimer:p-7S-p100:SCF-beta-TRCPNIK:p-S176,180-IKKA
dimer:p-7S-p100:RELBNIK:p-S176,180-IKKA
dimer:p-7S-p100:RELBNIK:p-S176,180-IKKA
dimer:p100:RELBNIK:p-S176,180-IKKA
dimer:p100:RELBNIK:p-S176,180-IKKA
dimer:p100:RELBNIK:p-S176,180-IKKA
dimerNIK:p-S176,180-IKKA
dimerNIK:p-S176,180-IKKA
dimerdimer:HIV gp120,HCV
gp E2oligomers:active
caspase-8:ASColigomers:active
caspase-8:ASCEfficient ubiquitination of phosphorylated p100 by SCF-beta-TRCP E3 ligase also requires the presence of the components of the NEDD8 pathway: UBA3 (NEDD8-activating enzyme E1 catalytic subunit), UBC12 (NEDD8-conjugating enzyme Ubc12 (E2)), NEDD8 (Neural precursor cell expressed developmentally down-regulated protein 8). NEDD8 binds and promotes a conformational change in CUL1 that may result in efficient formation of an E2-E3 complex, thus stimulating SCF complexes activity (Kawakami et al. 2001, Morimoto et al. 2000, Read et al. 2000).
IKK subunits have a N-term kinase domain a leucine zipper (LZ) motifs, a helix-loop-helix (HLH) and a C-ter NEMO binding domain (NBD). IKK catalytic subunits are dimerized through their LZ motifs. IKK beta is the major IKK catalytic subunit for NF-kB activation. Activated TAK1 phosphorylate IKK beta on S177 and S181 (S176 and S180 in IKK alpha) in the activation loop and thus activate the IKK kinase activity, leading to the IkB alpha phosphorylation and NF-kB activation.
Ferwerda et al. (2009) suggest that chronic mucocutaneous candidiasis may be caused by a genetic defect of CLEC7A. The mutation of nucleotide A-->C causes a change of amino acid 238 from tyrosine to a stop codon (Tyr238*), leading to the loss of the last nine amino acids of the carbohydrate-recognition domain (CRD). This mutated form of CLEC7A is poorly expressed and does not mediate beta-glucan binding, leading to defective production of cytokines after stimulation with beta-glucans or Candida albicans (Ferwerda et al. 2009).
Like other members of the Dectin-2 family, cytoplasmic region of CLEC6A has no obvious signalling motif and it associates with transmembrane adapter FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) to transduce a CLEC6A/Dectin-2 signalling.
Unlike the other Dectin-2 family members, CLEC4A has a long cytoplasmic tail with a classical immunoreceptor tyrosine based inhibitory signalling motif (ITIMs) (Flornes et al. 2004). CLEC4A with its ITIM motif mediates inhibitory signalling through activation of the phosphatases SHP1 and SHP2 (Kanazawa et al 2003, Meyer-Wentrup et al. 2009). Activation of CLEC4A on DCs or pDCs leads to inhibition of TLR8-mediated IL12 and TNF production, and TLR9-induced IFN-alpha production (Lambert et al. 2011, Meyer-Wentrup et al. 2008).
In humans, polymorphisms of CLEC4A have been associated with susceptibility to rheumatoid arthritis (Lorentzen et al. 2007).
CLEC4C lacks signalling motif in its cytoplasmic tail and associates with transmembrane adapter FCERG (High affinity immunoglobulin epsilon receptor subunit gamma) to induce intracellular signal transduction in a B-cell receptor (BCR)-like fashion employing SYK to regulate the immune functions of pDCs. The FCERG-SYK signalling pathway interferes with TLR9-induced activation of pDC, inhibiting type I IFN secretion (Cao et al. 2007, Dzionek et al. 2001, Rock et al. 2007, Riboldi et al. 2011).
bound to CBM
complex