Neddylation (Homo sapiens)
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Description
NEDD8 is a small ubiquitin-like molecule that is conjugated to substrate proteins through an E1 to E3 enzyme cascade similar to that for ubiquitin. The best characterized target of neddylation is the cullin scaffold subunit of cullin-RING E3 ubiquitin ligases (CRLs), which themselves target numerous cellular proteins for degradation by the proteasome (Hori et al, 1999; reviewed in Soucy et al, 2010; Lyedeard et al, 2013). The multisubunit CRL complexes are compositionally diverse, but each contains a scaffolding cullin protein (CUL1, 2, 3, 4A, 4B, 5, 7 or 9) and a RING box-containing E3 ligase subunit RBX, along with other adaptor and substrate-interacting subunits. RBX2 (also known as RNF7) interacts preferentially with CUL5, while RBX1 is the primary E3 for most other cullin family members (reviewed in Mahon et al, 2014). Neddylation of the cullin subunit increases the ubiquitination activity of the CRL complex (Podust et al, 2000; Read et al, 2000; Wu et al, 2000; Kawakami et al, 2001; Ohh et al, 2002; Yu et al, 2015). In addition to CRL complexes, a number of other less-well characterized NEDD8 targets have been identified. These include other E3 ubiquitin ligases such as SMURF1 and MDM2, receptor tyrosine kinases such as EGFR and TGF beta RII, and proteins that contribute to transcriptional regulation, among others (Xie et al, 2014; Watson et al, 2010; Oved et al, 2006; Zuo et al, 2013; Xirodimas et al, 2004; Singh et al, 2007; Abida et al, 2007; Liu et al 2010; Watson et al, 2006; Loftus et al, 2012; Aoki et al, 2013; reviewed in Enchev et al, 2015).
Like ubiquitin, NEDD8 undergoes post-translational processing to generate the mature form. UCHL3- or SENP8-mediated proteolysis removes the C-terminal 5 amino acids of NEDD8, generating a novel C-terminal glycine residue for conjugation to the cysteine residues in the E1, E2 enzymes or lysine residues in the substrate protein, usually the E3 NEDD8 ligase itself (Wada et al, 1998; reviewed in Enchev et al, 2015). Most substrates in vivo appear to be singly neddylated on one or more lysine residues, but NEDD8 chains have been formed on cullin substrates in vitro and on histone H4 in cultured human cells after DNA damage (Jones et al, 2008; Ohki et al, 2009; Xirodimas et al, 2008; Jeram et al, 2010; Ma et al, 2013; reviewed in Enchev et al, 2015). The significance of NEDD8 chains is still not clear.
NEDD8 has a single heterodimeric E1 enzyme, consisting of NAE1 (also known as APPBP1) and UBA3, and two E2 enzymes, UBE2M and UBE2F, which are N-terminally acetylated (Walden et al, 2003; Bohnsack et al, 2003; Huang et al, 2004; Huang et al, 2005; Huang et al, 2009; Scott et al, 2011a; Monda et al, 2013; reviewed in Enchev et al, 2015). All NEDD8 E3 enzymes reported to date also function as E3 ubiquitin ligases, and most belong to the RING domain class. The best characterized NEDD8 E3 enzymes are the CRL complexes described above. RBX1-containing complexes interact preferentially with UBE2M, while UBE2F is the E2 for RBX2-containing complexes (Huang et al, 2009; Monda et al, 2013).
Neddylation is regulated in vivo by interaction with DCUN1D proteins (also called DCNLs). The 5 human DCUN1D proteins interact both with cullins and with the NEDD8 E2 proteins and thereby increase the kinetic efficiency of neddylation (Kurz et al, 2005; Kurz et al, 2008; Scott et al, 2010; Scott et al, 2011a; Scott et al, 2014; Monda et al, 2013). Glomulin (GLMN) is another regulator of CRL function that binds to the neddylated cullin and competitively inhibits interaction with the ubiquitin E2 enzyme (Arai et al, 2003; Tron et al, 2012; Duda et al, 2012; reviewed in Mahon et al, 2014).
The multisubunit COP9 signalosome is the only cullin deneddylase, while SENP8 (also known as DEN1) contributes to deneddylation of other non-cullin NEDD8 targets (Cope et al, 2002; Emberley et al, 2012; Chan et al, 2008; Wu et al, 2003; reviewed in Wei et al, 2008; Enchev et al, 2015). In the deneddylated state, cullins bind to CAND1 (cullin associated NEDD8-dissociated protein1), which displaces the COP9 signalosome and promotes the exchange of the ubiquitin substrate-specific adaptor. This allows CRL complexes to be reconfigured to target other subtrates for ubiquitination (Liu et al, 2002; Schmidt et al, 2009; Pierce et al, 2013; reviewed in Mahon et al, 2014).
View original pathway at:Reactome.
Like ubiquitin, NEDD8 undergoes post-translational processing to generate the mature form. UCHL3- or SENP8-mediated proteolysis removes the C-terminal 5 amino acids of NEDD8, generating a novel C-terminal glycine residue for conjugation to the cysteine residues in the E1, E2 enzymes or lysine residues in the substrate protein, usually the E3 NEDD8 ligase itself (Wada et al, 1998; reviewed in Enchev et al, 2015). Most substrates in vivo appear to be singly neddylated on one or more lysine residues, but NEDD8 chains have been formed on cullin substrates in vitro and on histone H4 in cultured human cells after DNA damage (Jones et al, 2008; Ohki et al, 2009; Xirodimas et al, 2008; Jeram et al, 2010; Ma et al, 2013; reviewed in Enchev et al, 2015). The significance of NEDD8 chains is still not clear.
NEDD8 has a single heterodimeric E1 enzyme, consisting of NAE1 (also known as APPBP1) and UBA3, and two E2 enzymes, UBE2M and UBE2F, which are N-terminally acetylated (Walden et al, 2003; Bohnsack et al, 2003; Huang et al, 2004; Huang et al, 2005; Huang et al, 2009; Scott et al, 2011a; Monda et al, 2013; reviewed in Enchev et al, 2015). All NEDD8 E3 enzymes reported to date also function as E3 ubiquitin ligases, and most belong to the RING domain class. The best characterized NEDD8 E3 enzymes are the CRL complexes described above. RBX1-containing complexes interact preferentially with UBE2M, while UBE2F is the E2 for RBX2-containing complexes (Huang et al, 2009; Monda et al, 2013).
Neddylation is regulated in vivo by interaction with DCUN1D proteins (also called DCNLs). The 5 human DCUN1D proteins interact both with cullins and with the NEDD8 E2 proteins and thereby increase the kinetic efficiency of neddylation (Kurz et al, 2005; Kurz et al, 2008; Scott et al, 2010; Scott et al, 2011a; Scott et al, 2014; Monda et al, 2013). Glomulin (GLMN) is another regulator of CRL function that binds to the neddylated cullin and competitively inhibits interaction with the ubiquitin E2 enzyme (Arai et al, 2003; Tron et al, 2012; Duda et al, 2012; reviewed in Mahon et al, 2014).
The multisubunit COP9 signalosome is the only cullin deneddylase, while SENP8 (also known as DEN1) contributes to deneddylation of other non-cullin NEDD8 targets (Cope et al, 2002; Emberley et al, 2012; Chan et al, 2008; Wu et al, 2003; reviewed in Wei et al, 2008; Enchev et al, 2015). In the deneddylated state, cullins bind to CAND1 (cullin associated NEDD8-dissociated protein1), which displaces the COP9 signalosome and promotes the exchange of the ubiquitin substrate-specific adaptor. This allows CRL complexes to be reconfigured to target other subtrates for ubiquitination (Liu et al, 2002; Schmidt et al, 2009; Pierce et al, 2013; reviewed in Mahon et al, 2014).
View original pathway at:Reactome.
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DataNodes
E3 ubiquitin ligase
complex:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22E3 ubiquitin ligase
complex:MyrG-DCUN1D3E3 ubiquitin
ligase:COMMDs:CCDC22E3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1D1,2,4,5E3 ubiquitin
ligase:COMMDs:CCDC22E3 ubiquitin
ligase:COMMDs:CCDC22CRL E3 ubiquitin
ligases:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUND1,2,4,5E3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1D1,2,4,5E3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsAnnotated Interactions
E3 ubiquitin ligase
complex:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22E3 ubiquitin ligase
complex:MyrG-DCUN1D3E3 ubiquitin ligase
complex:MyrG-DCUN1D3E3 ubiquitin
ligase:COMMDs:CCDC22E3 ubiquitin
ligase:COMMDs:CCDC22E3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1D1,2,4,5E3 ubiquitin
ligase:COMMDs:CCDC22E3 ubiquitin
ligase:COMMDs:CCDC22E3 ubiquitin
ligase:COMMDs:CCDC22CRL E3 ubiquitin
ligases:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUND1,2,4,5E3 ubiquitin
ligase:COMMDs:CCDC22:DCUND1,2,4,5E3 ubiquitin
ligase:COMMDs:CCDC22:DCUND1,2,4,5E3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsE3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1D1,2,4,5E3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1D1,2,4,5E3 ubiquitin
ligase:COMMDs:CCDC22:DCUN1DsUBE2F is the E2 responsible for the transfer of NEDD8 to the CUL5:RBX2 E3 ligase complex, while UBE2M is specific for RBX1-containing E3 ligase complexes formed with CUL1-4 (Huang et al, 2009; reviewed in Mahon et al, 2014).
CUL5 RING complexes target a variety of cellular proteins for ubiquitination and degradation, including receptor and non-receptor tyrosine kinases, signaling molecules transcriptional regulators (reviewed in Okumura et al, 2016). CRL5 complexes are also hijacked by viruses such as HIV and HPV, among others. Interaction with viral proteins redirects the ubiquitin ligase complex, targeting host proteins such as immune factors and in this way promoting viral propagation (reveiwed in Mahon et al, 2014).
CRL4 complexes ubiquitinate target proteins involved in processes such as cell cycle progression, DNA repair and replication, cell growth and metabolism (reviewed in Hannah and Zhou, 2015; Sang et al, 2015). CRL4 complexes are also hijacked by a number of viruses, redirecting the ubiquitin ligase complex to target host proteins and in this way promoting viral propagation (reviewed in Mahon et al, 2014). Note that because many of the key CRL4 ubiquitin targets are nuclear, these complexes are depicted in the nucleus. Cytoplasmic targets have also been identified, however (reviewed in Hannah and Zhou, 2015).
CUL9 is 60% identical to CUL7, another atypical mammalian cullin family member, but more distantly related to CUL1, 2, 3, 4A,4B and 5. CUL9 and CUL7 have been shown to form a heterodimer in vivo, and both interact with p53 (Skaar et al, 2007; Andrews et al, 2006; Nikolaev et al, 2003). CUL9 ubiquitinates BIRC5 (also known as Survivin), a protein with roles in cellular proliferation and inhibition of apoptosis. CUL9-mediated ubiquitination of BIRC5 is inhibited by the 3M complex, which consists of CUL7, CCDC8 and OBSL1 (Li et al, 2014).