The virus particle initially associates with a human host cell by binding to sialic acid-containing receptors on the host cell surface. The bound virus is endocytosed by one of four distinct mechanisms. The low endosomal pH sets in motion a number of steps that lead to viral membrane fusion mediated by the viral hemagglutinin (HA) protein, and the eventual release of the uncoated viral ribonucleoprotein complex into the cytosol of the host cell. The ribonucleoprotein complex is transported through the nuclear pore into the nucleus. Once in the nucleus, the incoming negative-sense viral RNA (vRNA) is transcribed into messenger RNA (mRNA) by a primer-dependent mechanism. Replication occurs via a two step process. A full-length complementary RNA (cRNA), a positive-sense copy of the vRNA, is first made and this in turn is used as a template to produce more vRNA. The viral proteins are expressed and processed and eventually assemble with vRNAs at budding sites within the host cell membrane. The viral protein complexes and ribonucleoproteins are assembled into viral particles and bud from the host cell, enveloped in the host cell's membrane.
This release contains a framework for the further annotation of the viral life-cycle.
View original pathway at:Reactome.</div>
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Viral RNA bound by polymerase PB1-PB2-PA subunits, primed by a 5' end cap cleaved from a host mRNA, and the second ribonucleotide (a G) complementary to a the vRNA second position (a C, Beaton, 1981; Krug, 1981; Li, 2001).
A mature mRNA that has been 3' cleaved, subsequently polyadenylated, and a m7G 5' cap. The m7G has been removed or snatched. This product was derived from an intronless transcript.
Heterotrimeric influenza viral polymerase complex consisting of PB1, PB2, and PA; although capable of being imported into the nucleus independently, the three subunits of the influenza polymerase assemble in the nucleus to form a mature ternary polymerase complex that binds viral vRNA or cRNA (reviewed in Buolo et al., 2006).
The 5' and 3' ends of the vRNA bound to the PB1 subunit of the viral RNA polymerase; PB2 bound to the methylated cap on a host pre-mRNA amino acids (Cianci, 1995; Brownlee, 2002; Honda, 1999).
Influenza viruses bind via their surface HA (hemagglutinin) to sialic acid in alpha 2,3 or alpha 2,6 linkage with galactose on the host cell surface. Sialic acid in 2,6 linkages is characteristic of human cells while 2,3 linkages are characteristic of avian cells. The specificity of influenza HA for sialic acid in alpha 2,6 or alpha 2,3 linkages is a feature restricting the transfer of influenza viruses between avian species and humans. This species barrier can be overcome, however. Notably, passaged viruses adapt to their host through mutation in the receptor binding site of the viral HA gene.
The host cell mRNA bound to viral RNA polymerase PB2 subunit is cleaved by the viral RNA polymerase PB1 subunit's endonuclease activity, and the capped 5' end plus 10-13 nucleotides of the host mRNA remains bound to the polymerase complex (Plotch, 1981; Krug, 1981; Hagen, 1994; Cianci, 1995, Li, 1998; Li, 2001). Viral mRNA may be protected against cap-snatching by the polymerase complex itself, which tightly binds capped viral mRNA (Shih, 1996). A guanine residue, complementary to a cytosine in the vRNA, is added to the host-derived cap, catalyzed by the RNA polymerase activity of the PB1 viral RNA polymerase subunit (Beaton, 1981; Toyoda, 1986).
The eight influenza virus genome segments never exist as naked RNA but are associated with four viral proteins to form viral ribonucleoprotein complexes (vRNPs). The major viral protein in the RNP complex is the nucleocapsid protein (NP), which coats the RNA. The remaining proteins PB1, PB2 and PA bind to the partially complementary ends of the viral RNA, creating the distinctive panhandle structure. The influenza viral NP behaves like a nuclear localization sequence (NLS) containing protein. The RNP docks at the nuclear envelope only in the presence of the heterodimeric karyopherin alpha and beta complex. Here karyopherin alpha recognizes the RNP.
The influx of H+ ions into the virion disrupts protein-protein interactions, resulting in the release of the viral RNP from the viral matrix (M1) protein. The uncoating process is complete with the appearance of free RNP complexes in the cytosol.
A poly-uridine sequence motif, consisting in most cases of 5-7 U residues, abuts the "panhandle" duplex structure in the vRNA; this sequence is approximately 16 nucleotides from the 5' end of this RNA duplex structure within the vRNA promoter. Encountering this signal, the viral RNA polymerase stutters, leading to the synthesis of a poly-A tail on the viral mRNA (Robertson, 1981; Luo, 1991; Li,1994; Poon, 1998; Zheng et al. 1999).
The concerted structural change of several hemagglutinin molecules opens a pore through which the viral RNP will be able to pass into the host cell cytosol.
Once the viral RNP and heterodimeric karyopherin complex has been transported into the nucleus the RNP dissasociates from the heterodimeric karyopherins.
The fusion peptide of its HA2 subunit interacts with the endosome membrane. The transmembrane domain of the HA2 is inserted into the viral membrane and the fusion peptide is inserted into the endosomal membrane. In the acidic pH structure of HA the two ends of the HA complex are in juxtaposition.
The uncoating of influenza viruses in endosomes is blocked by changes in pH caused by weak bases (e.g. ammonium chloride and chloroquine) or ionophores (e.g. monensin). Effective uncoating is also dependent on the presence of the viral M2 ion channel protein. Early on it was recognized that amantadine and rimantadine inhibit replication immediately following virus infection. Later it was found that the virus-associated M2 protein allows the influx of H+ ions from the endosome into the virion. This disrupts protein-protein interactions, resulting in the release of viral RNP free of the viral matrix (M1) protein. Amantadine and rimantadine have been shown to block the ion channel activity of the M2 protein and thus uncoating.
The eight influenza virus genome segments are associated with four viral proteins to form viral ribonucleoprotein complexes (vRNPs). The major viral protein in the RNP complex is the nucleocapsid protein (NP), which coats the RNA. The remaining proteins PB1, PB2 and PA bind to the partially complementary ends of the viral RNA. The influenza viral NP behaves like a nuclear localization sequence (NLS) containing protein. The RNP docks at the nuclear envelope only in the presence of the heterodimeric karyopherin alpha and beta complex. Once the NLS is recognized by karyopherin alpha the karyopherin beta subunit joins the complex.
The 5' end of the vRNA associates with a binding site on the PB1 subunit of the viral RNA polymerase, distinct from the 3' vRNA binding site, which is subsequenty bound forming a loop. These binding events set off allosteric conformational changes in the trimeric polymerase complex that induce PB2 binding of the methylated cap on a host pre-mRNA (Plotch, 1981; Cianci, 1995; Li, 1998; Brownlee, 2002; Kolpashchikov, 2004). PB2 amino acids 242-282 and 538-577 are involved in cap binding (Honda, 1999). Direct or indirect interaction with active, transcribing host RNA polymerase II is thought to supply host mRNA for the caps (Bouloy, 1978; Engelhardt, 2005).
Catalyzed by the RNA polymerase activity of the viral PB1 subunit, an mRNA complementary to the bound vRNA is synthesized (Plotch, 1977). PA and PB2 move down the growing mRNA in complex with PB1, with PB2 possibly dissociating from the cap (Braam, 1983). However, the 5’ end of the vRNA may remain bound during elongation as the template is threaded through in a 3’ to 5’ direction until a polyadenylation signal is encountered (Poon, 1998; Zheng, 1999).
These RNPs (10-20nm wide) are too large to passively diffuse into the nucleus and therefore, once released from an incoming particle they must rely on the active import mechanism of the host cell nuclear pore complex (NPC). Once the RNP heterodimeric karyopherin complex docks at the NPC, it is transported into the nucleus.
Virus NEP/NS2 interacts with human CRM1 (hCRM1), possibly dependent on a nuclear export signal (NES) motif in the NEP/NS2 N-terminal region (O'Neill, 1998; Neumann, 2000). The CRM1/exportin-1 pathway is a cellular mechanism for nuclear export, with CRM1 interacting with the Ran small GTPase and a cargo molecule's leucine-rich NES (Fukuda, 1997; Petosa, 2004). Leptomycin B, which specifically inhibits hCRM1, blocks export of viral RNP (Elton, 2001; Ma, 2001; Watanabe, 2001). Thus, NEP/NS2 interaction with cellular nuclear export machinery is essential for nuclear export of vRNP complexes and influenza virus release. A role for NP protein interaction with export machinery has also been proposed (Elton, 2001).
The hemagglutinin of influenza virus is palmitoylated with long-chain fatty acids. Palmitoylation of HA is believed to occur in the cis golgi network (Veit 1993), shortly after trimerisation of the molecule, and before cleavage of the HA into HA1 and HA2. HA is palmitoylated through thioester linkages at three cysteine residues located in the cytoplasmic domain and at the carboxy-terminal end of the transmembrane region. Lack of acylation has no obvious influence on the biological activities of HA.
The final step in the budding process is the fusion of the lipid membrane surrounding the virion core, producing an extracellular enveloped virus particle (Nayak et al. 2004).
Influenza virus buds preferentially from lipid rafts (Scheiffele et al, 1999). NA protein individually accumulates at, and is selectively incorporated into rafts (Kundu et al., 1996). The signals for raft association lie within the transmembranse domain (TMD), (Barman et al., 2001, Barman et al., 2004), and raft association of NA has been shown to be essential for efficient virus replication. This is believed to be due to a requirement for a concentration of NA at specific areas of the plasma membrane to support a level of NA incorporation into budding particles sufficient to allow for efficient virus release (Barman et al., 2004).
The release of influenza virus particles after seperation of the virus and infected cell membrane is an active process. During the budding process, HA on the surface of the newly budding virion binds to cell surface molecules containing sialic acid residues as seen during attachment. The NA glycoproteins neuraminidase activity is essential to cleave the link between the HA and sialic acid on the surface of the host cell from which the budding virus is emeging from. Thus the NA mediated cleavage of sialic acid residues terminally linked to glycoproteins and glycolipids is the final step in releasing the virus particle from the host cell. This essential role of NA in release of virus particle has been demonstrated with the use of NA inhibitors (Palese, 1976; Luo, 1999; Garman, 2004), ts NA mutant viruses (Palese, 1974) and with viruses lacking NA activity (Liu, 1995). In all cases, viruses remain bound to the cell surface in clumps in the absence of NA enzymatic activity, resulting in loss of infectivity. Addition of exogenous sialidase results in virus release and recovery of infectivity. The sialidase activity of the NA is also important for removing sialic acid from the HA on virus particles, if this is not removed, virus particles aggregate.
Trimerisation of the fully folded and fully oxidised HA monomer is thought to occur in the endoplasmic reticulum and ERGIC compartment, following dissociation of HA from calnexin. Trimerisation is generally thought to be the final step in HA maturation occurring in the endoplasmic reticulum before transport to the Golgi apparatus, although Yewdell et al (1988) provide data suggesing that trimerisation may occur within the Golgi.
Viral RNP, bound by M1 and NEP/NS2 interacting with CRM1, are shuttled through the nuclear pore into the cytoplasm (Martin, 1991; O'Neill, 1998; Buolo, 2006). This mechanism may resemble export of HIV-1 ribonucleoprotein, where the HIV-1 Rev export protein interacts with CRM1 (Askjaer, 1998). A number of cofactors are implicated in CRM1-mediated export, including the small GTPase Ran, Ran-binding proteins 1 and 3, and a guanine nucleotide exchange factor (Nilsson, 2001; Nemergut, 2002; Petosa, 2004). Ternary CRM1-cofactor-cargo complexes likely interact transiently with nuclear pore proteins (nucleoporins) as they traverse the pore (reviewed in Suntharalingam, 2003). RanGTP is hydrolyzed to RanGDP in the cytoplasm, an activity that can be stimulated by NEP/NS2 (Akarsu, 2003). Influenza infection activates Raf/MEK/ERK signaling, which is necessary for NEP/NS2-mediated export of viral RNP (Pleschka, 2001; Marjuki, 2006). Influenza vRNP complexes released into the cytoplasm do not re-enter the nucleus, as they are thought to remain bound by M1, preventing re-import (Martin, 1991). It has been suggested that M1 binding of zinc cations could distinguish M1 bound to the vRNP from polymerized, matrix M1 present in nascent virions (Elster, 1994).
There is evidence that NP alone is intrinsically targeted to the apical plasma membrane and associates with lipid rafts in a cholesterol-dependent manner, which suggests that RNPs could reach the assembly site independently of the other viral components.
The integral membrane protein HA is synthesized on membrane-bound ribosomes and subsequently transported across the endoplasmic reticulum, where it is folded, glycosylated, and assembled into a trimer.
Structural characterization of NEP/NS2 suggests that acidic residues in the C-terminus of NEP/NS2 bind to M1, with Trp78 critical for interaction (Ward, 1995; Yasuda, 1993; Akarsu, 2003).
There is evidence for the association of M1 with lipid rafts in influenza infected cells, whereas M1 expressed alone remains soluble (Ali et al., 2000; Zhang and Lamb, 1996), suggesting association of M1 with other viral proteins in targetting to the cell membrane. Coexpression of HA and NA together with M1 has been shown to promote raft association of M1. This association requires the TMD and cytoplasmic tails of HA and NA (Ali et al, 2000; Zhang et al, 2000). This is consistent with M1 becoming associated with HA and NA during their passage through the exocytic pathway to raft domains in the apical membrane. alternatively M1 may use the cytoskeleton to reach the virus assembly site, as M1 interacts with cytoskeletal components (Alvalos et al., 1997). The M1 interaction depends on the presence of RNP and is most likely mediated by direct binding of F-actin by NP (Digard et al., 1999).
The random incorporation model as its name suggests proposes that there is no selection at all on which vRNPs are packaged. It is assumed that each vRNP has equal probability of being packaged, and that if enough vRNPS are packaged a particular percentage of budding virions will receive at least one copy of each genome segment. This model is supported by evidence that infectious virions may possess more than eight vRNPs assuring the presence of a full complement of eight vRNPs in a significant percentage of virus particles. Mathematical analysis of packaging suggested that twelve RNA segments would need to be packaged in order to obtain approximately 10% of virus particles that are fully infectious (Enami, 1991), a number that is compatible with experimental data (Donald, 1954). Due to the low amount of RNA per virion (estimated at 1-2% w/w), enumeration of the precise number of RNAs packaged in a virion is difficult.
Tetramerisation of the NA occurs in the ER following an initial dimerisation step. Tetramerisation is believed to be dependant on glycosylation of the NA molecules
Glycosylation of NA occurs within the endoplasmic reticulum and is believed to be neccessary for proper tetramerization of the NA dimers. Sugar residues become attached to four of the five potential glycosylation sites in the head of N1 neuraminidase (Hausman et al., 1997).
The ectodomain of HA is translocated into the ER lumen, where it undergoes a series of folding events mediated by the formation of disulfide bonds and glycosylation reactions. The formation of a discrete intermediate species of highly folded monomeric protein preceeds trimerisation. The folding process is efficient and rapid, with greater than 90% of the protein trafficked to the golgi apparatus; and mature HA0 subunits appearing in a matter of a few minutes. Calnexin and calreticulin have been identified as cellular lectins which interact transiently with newly synthesized HA by attaching to partially trimmed N-linked oligosaccharides (Herbert et al., 1997), facilitating correct folding of the HA molecule.
The M2 from influenza A virus is a 97-residue protein with a single transmembrane helix that associates to form a tetramer in the endoplasmic reticulum (Salom et al, 2000). A 15-20-residue segment C-terminal to the membrane-spanning region has been postulated to aid in the stabilization of the tetrameric assembly (Kochendoerfer et al 1999).
Virion vRNP is capable of synthesizing cRNA immediately following entry into the cell nucleus (Vreede, 2006). The PB1 subunit principally catalyzes extension (Nakagawa, 1996). However, cRNA does not accumulate until later in the infection process, possiby requiring NP and the trimeric polymerase for stabilization (Vreede, 2004). The vRNA template is released.
The viral polymerase complex produces positive-sense viral mRNA with host-cell derived 5' methyl caps. Capped viral mRNAs are selectively exported from the host cell nucleus through a currently unclear mechanism that may rely on components of the host cell mRNA export machinery (Chen, 2000; Engelhardt, 2006). Polyadenylation of viral mRNA appears be required for influenza mRNA export (Poon, 2000). A coupling of viral mRNA export with cellular pre-mRNA processing complexes, recruited by phosphorylation of host RNA polymerase II C-terminal domain which interacts with the viral polymerase (Engelhardt, 2005), has been proposed as controlling the export of a subset (M1, HA, and NS1, but not NP) of viral mRNA from the nucleus (Amorim, 2007).
The nascent vRNP complexes, one for each gene segment, contain the negative-sense viral RNA and polymerase proteins (PB1, PB2, PA, and NP). In a model using negative-sense viral RNP reconstituted from transfected cells, there are multiple NP complexes and one polymerase complex arranged along a closed vRNA loop (Area et al., 2004). The three-dimensional structure of NP has revealed that three NP molecules form a stable trimer, interacting through beta-sheets b5, b6, and b7 in the C-terminal domain of the protein (Ye, 2006), with the viral RNA wrapping around the outside of the complex. Viral RNA from purified virions is present in an RNase-sensitive complex with NP and PB1, PB2, and PA, consistent with this structural model (Baudin et al, 1994; Ruigrok et al., 1995; Klumpp et al., 1997). It is not clear what controls the fate of vRNP, whether it is destined to become a template for transcription, for replication, or for export into the cytoplasm for packaging into virions at the plasma membrane, nor how distinct sub-nuclear localization and NP distribution at the nuclear matrix might mark, or polarize, a vRNP for export (Elton, 2005; Takizawa et al., 2006).
For most influenza A strains (such as PR8), the PB1 mRNA segment produces a second protein, PB1-F2, from the +1 open reading frame (Chen, 2001). PB1-F2 is a pro-apoptotic, mitochondria-localized protein (Chen, 2001; Gibbs, 2003) that oligomerizes (Bruns, 2007) and sensitizes cells to death in concert with the mitochondrial ANT3 and VDAC proteins (Zamarin, 2005).
M1 protein binds to viral RNP through its C-terminal domain (Baudin, 2001). The influenza M1 protein accumulates in the infected cell nucleus through a nuclear localization signal (NLS) RKLKR (residues 101-105) in its N-terminus (Ye, 1999). A host cell protein, HSP70, is thought to inhibit M1 binding at nonpermissive temperatures (Hirayama et al., 2004).
The viral polymerase complex produces positive-sense viral mRNA with host-cell derived 5' methyl caps. Alternately spliced mRNA transcribed from M and NS vRNA segments 7 and 8, producing the spliced mRNA for M2 and NEP/NS2, respectively, are thought to be coupled to the cellular splicing and export mechanisms (Lamb, 1980; Lamb, 1981; Chen, 2000; Li, 2001). As segments 7 and 8 each encode two proteins, splicing must be regulated allowing for alternative mRNAs, with the spliced products in the minority (approximately 10%). M1 splicing may be regulated by the viral polymerase and the cellular SR splicing protein SF2/ASF (Shih, 1995; Shih, 1996); while NS1 splicing appears to be regulated by the viral mRNA intrinsically (Alonso-Caplen, 1991; Valcarel, 1991).
The mature ternary influenza viral polymerase complex consists of PB1, PB2, and PA. The N-terminus of PB1 (residues 1-48) interacts with PB2, and amino acids 506-659 in PB1 interact with the PA subunit (Gonzalez, 1996; Perez, 2001). Although monomeric PB1, PB2 and PA, as well as PB1-PB2 and PB1-PA dimers are likely to exist in infected cells, it is believed that most of the polymerase proteins are assembled into the trimeric PB1-PB2-PA complex (Detjen, 1987). Newly synthesized subunits of the polymerase are imported into the nucleus through nuclear localization signals (NLS), which interact with cellular importin family proteins (Jones, 1986; Buolo, 2006). Importin beta-3 (Ran binding protein 5) facilitates nuclear import of PB1 and a PB1-PA dimer (Deng, 2006); coexpression of PA with PB1 was shown to enhance the import of PB1 (Fodor, 2004). A PB1-PB2 dimer has been found to interact with the molecular chaperone heat shock protein 90 (HSP90) to facilitate import (Naito, 2007). The three subunits assembled in the nucleus form a mature ternary polymerase complex that binds viral vRNA or cRNA (Jones, 1986; Buolo, 2006).
Viral vRNA, complexed with NP protein, is bound by the trimeric viral polymerase complex in a stable secondary structure-dependent manner, referred to as a panhandle, fork or cork-screw (Fodor, 1994; Brownlee, 2002; Park, 2003; Crow, 2004). This RNA structure is made of both the 5’ and 3' ends of the vRNA. The polymerase is thought to first bind the 5' end of the vRNA and then the 3' end. Synthesis of cRNA initiates without a host cell methylated RNA cap as a primer (Beaton, 1986; Galarza, 1996; Deng, 2006; Engehardt, 2006).
Spliced and unspliced viral mRNA exported into the cytoplasm are translated by the host cell ribosomal translation machinery (reviewed in Kash, 2006). At least ten viral proteins are synthesized: HA, NA, PB1, PB2, PA, NP, NS1, NEP/NS2 (from spliced NS mRNA), M1, and M2 (from spliced M mRNA). The abundance of each of these proteins is thought to be controlled by differential mRNA abundances and stability (Tekamp, 1980; Hatada, 1989). As the localization of the nascent polypeptides is different between viral proteins with transmembrane domains (HA, NA and M2, which translocate to the ER and are transported through the Golgi to the plasma membrane) and soluble viral proteins (such as NP, the polymerase subunits, and NS1), mechanisms linking the translation of particular viral mRNA with subsequent protein localization rely on signal sequences recognized by the cell.
vRNA is synthesized from the complementary cRNA strand by the trimeric polymerase complex, and bound by free NP protein (Honda, 1988; Mikulasova, 2000; Neumann, 2004). The PB1 subunit, with PA, catalyzes extension (Nakagawa, 1996). The cRNA is released.
Viral genomic RNA (vRNA) and complementary RNA (cRNA) are likely bound by the influenza nucleoprotein (NP) immediately upon synthesis. Although two nuclear localization signals have been mapped in the NP, an unconventional N-terminal NLS and a bipartite NLS within amino acids 198-216 (Wang, 1997; Neumann, 1997; Ozawa, 2007), the crystal structure of the NP suggests that only the unconventional NLS is exposed and can be used as a functional NLS (Ye, 2006). This unconvenetional NLS interacts with importins alpha-1 and -2 (Cros et al., 2005; Wang et al., 1997; Buolo et al., 2006). The three-dimensional structure of NP has revealed that NP molecules associate as a trimer, interacting through beta-sheets b5, b6, and b7 in the C-terminal domain of the protein; the viral RNA likely wraps around the outside of the complex (Ye, 2006).
Initiation of synthesis of the viral genomic RNA (vRNA) is thought to require hairpin (or panhandle/corkscrew) RNA loop structures formed by both the 5' and 3' ends of the cRNA (Pritlove, 1995; Crow, 2004; Park, 2003; Deng, 2006). The cRNA promoter has a similar structure to the vRNA promoter, but slight sequence differences are believed to result in a stronger cRNA promoter. As with the vRNA promoter, the polymerase is thought to first bind to the 5' end of the cRNA, then to the 3' end, and subsequently initiate RNA synthesis.
In the cases of spliced, polyadenylated mRNA transcribed from M (segment 7) and NS (segment 8) vRNA templates (producing the spliced mRNA for M2 and NS2/NEP, respectively), export may be coupled to aspects of the cellular splicing and export mechanisms (Chen, 2000; Alonso-Caplan et al, 1992; Amorim, 2006). Simultaneously, the export of cellular mRNA appear to be inhibited by the viral NS1 protein, which binds to the cellular cleavage and polyadenylation specificity factor (CPSF), preventing polyadenylation and completion of pre-mRNA processing (Nemerof et al., 1998; Fortes, 1994; Lu, 1994; Li, 2001).
Influenza virus buds preferentially from lipid rafts (Scheiffele et al, 1999). NA protein individually accumulates at, and is selectively incorporated into rafts (Kundu et al., 1996). The signals for raft association lie within the transmembranse domain (TMD), (Barman et al., 2001, Barman et al., 2004), and raft association of NA has been shown to be essential for efficient virus replication. This is believed to be due to a requirement for a concentration of NA at specific areas of the plasma membrane to support a level of NA incorporation into budding particles sufficient to allow for efficient virus release (Barman et al., 2004).
The integral membrane protein M2 is synthesized on membrane-bound ribosomes and subsequently transported across the ER, where it is folded and assembled into a tetramer.
The integral membrane protein NA is synthesized on membrane-bound ribosomes and subsequently transported across the ER where it is folded and glycosylated. Subsequently NA is assembled into a tetramer.
Palmitoylation of influenza A M2 occurs in the ER, or cis golgi network, following tetramerisation. The palmitoylation reaction proceeds via a labile thioester type bond at a specific residue of M2 (Sugrue et al., 1990).
As influenza viruses bud from the plasma membrane of infected cells, complete virions are not seen inside cells. In polarized epithelial cells, assembly and budding of influenza occurs from the apical plasma membrane (Schmitt, 2004). For efficient assembly, all virion components must accumulate at the budding site, and it is believed that the viral glycoprotein accumulation determines the site of virus assembly and budding (Nayak, 2004). M1 is thought to be the bridge between the envelope glycoproteins and the RNPs for assembly (Schmitt, 2004). M2 is also required, because if it is not present RNPs are not packaged into budding virions (McCown, 2005), however it role is not known.
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A Viral Particle Docked At The Endocytic Vesicle Membrane With An
Open Porepalmitylated and folded HA trimer:Lipid Raft
Complexpalmitylated and folded HA trimer:Lipid Raft
Complexpalmitylated and
folded HA trimerpalmitylated and
folded HA trimerBilayer Membrane Rich In Sphingolipids And
CholesterolEnvelope Inserted Into The Endocytic
Vesicle MembraneParticle Docked At The Endocytic Vesicle Membrane
With An Open PoreParticle Docked At The Endocytic
Vesicle MembraneParticle With A Fusion Competent
HA2Transcription
Complextranscript derived mRNA with m7G cap
removedtranscript derived
mRNAPolymerase II
(phosphorylated):TFIIF:capped pre-mRNAComplex:Karyopherin
alphaalpha:Karyopherin
beta complexalpha:Karyopherin
beta complexInfluenza A Viral
ParticleInfluenza A Viral
ParticleAnnotated Interactions
A Viral Particle Docked At The Endocytic Vesicle Membrane With An
Open PoreA Viral Particle Docked At The Endocytic Vesicle Membrane With An
Open Porepalmitylated and folded HA trimer:Lipid Raft
Complexpalmitylated and folded HA trimer:Lipid Raft
Complexpalmitylated and folded HA trimer:Lipid Raft
Complexpalmitylated and
folded HA trimerpalmitylated and
folded HA trimerpalmitylated and
folded HA trimerBilayer Membrane Rich In Sphingolipids And
CholesterolEnvelope Inserted Into The Endocytic
Vesicle MembraneParticle Docked At The Endocytic Vesicle Membrane
With An Open PoreParticle Docked At The Endocytic Vesicle Membrane
With An Open PoreParticle Docked At The Endocytic Vesicle Membrane
With An Open PoreParticle Docked At The Endocytic
Vesicle MembraneParticle Docked At The Endocytic
Vesicle MembraneParticle With A Fusion Competent
HA2Particle With A Fusion Competent
HA2Transcription
ComplexTranscription
Complextranscript derived mRNA with m7G cap
removedtranscript derived
mRNAPalmitoylation of HA is believed to occur in the cis golgi network (Veit 1993), shortly after trimerisation of the molecule, and before cleavage of the HA into HA1 and HA2. HA is palmitoylated through thioester linkages at three cysteine residues located in the cytoplasmic domain and at the carboxy-terminal end of the transmembrane region. Lack of acylation has no obvious influence on the biological activities of HA.
Polymerase II
(phosphorylated):TFIIF:capped pre-mRNAComplex:Karyopherin
alphaComplex:Karyopherin
alphaalpha:Karyopherin
beta complexalpha:Karyopherin
beta complexalpha:Karyopherin
beta complexalpha:Karyopherin
beta complexInfluenza A Viral
ParticleInfluenza A Viral
ParticleInfluenza A Viral
ParticleInfluenza A Viral
Particle