AC MF_04078; DC Protein; auto TR HAMAP; MF_04078; -; 1; level=0 XX Names: NEF_HIV XX ID NEF DE RecName: Full=Protein Nef; DE AltName: Full=3'ORF; DE AltName: Full=Negative factor; DE Short=F-protein; DE Contains: DE RecName: Full=C-terminal core protein; GN Name=nef; XX CC -!- FUNCTION: Factor of infectivity and pathogenicity, required for optimal CC virus replication. Alters numerous pathways of T-lymphocyte function CC and down-regulates immunity surface molecules in order to evade host CC defense and increase viral infectivity. Alters the functionality of CC other immunity cells, like dendritic cells, monocytes/macrophages and CC NK cells. CC -!- FUNCTION: In infected CD4(+) T-lymphocytes, down-regulates the surface CC MHC-I, mature MHC-II, CD4, CD28, CCR5 and CXCR4 molecules. Mediates CC internalization and degradation of host CD4 through the interaction of CC with the cytoplasmic tail of CD4, the recruitment of AP-2 (clathrin CC adapter protein complex 2), internalization through clathrin coated CC pits, and subsequent transport to endosomes and lysosomes for CC degradation. Diverts host MHC-I molecules to the trans-Golgi network- CC associated endosomal compartments by an endocytic pathway to finally CC target them for degradation. MHC-I down-regulation may involve AP-1 CC (clathrin adapter protein complex 1) or possibly Src family kinase- CC ZAP70/Syk-PI3K cascade recruited by PACS2. In consequence infected CC cells are masked for immune recognition by cytotoxic T-lymphocytes. CC Decreasing the number of immune receptors also prevents reinfection by CC more HIV particles (superinfection). Down-regulates host SERINC3 and CC SERINC5 thereby excluding these proteins from the viral particles. CC Virion infectivity is drastically higher when SERINC3 or SERINC5 are CC excluded from the viral envelope, because these host antiviral proteins CC impair the membrane fusion event necessary for subsequent virion CC penetration. CC -!- FUNCTION: Bypasses host T-cell signaling by inducing a transcriptional CC program nearly identical to that of anti-CD3 cell activation. CC Interaction with TCR-zeta chain up-regulates the Fas ligand (FasL). CC Increasing surface FasL molecules and decreasing surface MHC-I CC molecules on infected CD4(+) cells send attacking cytotoxic CD8+ T- CC lymphocytes into apoptosis. CC -!- FUNCTION: Plays a role in optimizing the host cell environment for CC viral replication without causing cell death by apoptosis. Protects the CC infected cells from apoptosis in order to keep them alive until the CC next virus generation is ready to strike. Inhibits the Fas and TNFR- CC mediated death signals by blocking MAP3K5/ASK1. Decreases the half-life CC of TP53, protecting the infected cell against p53-mediated apoptosis. CC Inhibits the apoptotic signals regulated by the Bcl-2 family proteins CC through the formation of a Nef/PI3-kinase/PAK2 complex that leads to CC activation of PAK2 and induces phosphorylation of host BAD. CC -!- FUNCTION: Extracellular Nef protein targets CD4(+) T-lymphocytes for CC apoptosis by interacting with CXCR4 surface receptors. CC -!- SUBUNIT: Monomer; cytosolic form. Homodimer; membrane bound form. CC Interacts with Nef associated p21-activated kinase (PAK2); this CC interaction activates PAK2. Associates with the Nef-MHC-I-AP1 complex; CC this complex is required for MHC-I internalization. Interacts (via C- CC terminus) with host PI3-kinase. Interacts with host PACS1; this CC interaction seems to be weak. Interacts with host PACS2. Interacts with CC host LCK and MAPK3; these interactions inhibit the kinase activity of CC the latter. Interacts with host ATP6V1H; this interaction may play a CC role in CD4 endocytosis. Associates with the CD4-Nef-AP2 complex; this CC complex is required for CD4 internalization. Interacts with host AP2 CC subunit alpha and AP2 subunit sigma2. Interacts with TCR-zeta chain; CC this interaction up-regulates the Fas ligand (FasL) surface expression. CC Interacts with host HCK, LYN, and SRC; these interactions activate the CC Src family kinases. Interacts with MAP3K5; this interaction inhibits CC the Fas and TNFR-mediated death signals. Interacts with beta-COP and CC PTE1. Interacts with human RACK1; this increases Nef phosphorylation by CC PKC. Interacts with TP53; this interaction decreases the half-life of CC TP53, protecting the infected cell against p53-mediated apoptosis. CC -!- SUBCELLULAR LOCATION: Host cell membrane; Lipid-anchor; Cytoplasmic CC side. Virion. Secreted. Host Golgi apparatus membrane. Note=TGN CC localization requires PACS1. Associates with the inner plasma membrane CC through its N-terminal domain. Nef stimulates its own export via the CC release of exosomes. Incorporated in virions at a rate of about 10 CC molecules per virion, where it is cleaved. CC -!- INDUCTION: Expressed early in the viral replication cycle. CC -!- DOMAIN: The N-terminal domain is composed of the N-myristoyl glycine CC and of a cluster of positively charged amino acids. It is required for CC inner plasma membrane targeting of Nef and virion incorporation, and CC thereby for infectivity. This domain is also involved in binding to CC TP53. CC -!- DOMAIN: The SH3-binding domain constituted of PxxP motifs mediates CC binding to several Src family proteins thereby regulating their CC tyrosine kinase activity. The same motifs also mediates the association CC with MAPK3, PI3-kinase and TCR-zeta. CC -!- DOMAIN: The dileucine internalization motif and a diacidic motif seem CC to be required for binding to AP-2. CC -!- DOMAIN: The acidic region binds to the sorting protein PACS-2, which CC targets Nef to the paranuclear region, enabling the PxxP motif to CC direct assembly of an SFK/ZAP-70/PI3K complex that accelerates CC endocytosis of cell-surface MHC-I. CC -!- PTM: The virion-associated Nef proteins are cleaved by the viral CC protease to release the soluble C-terminal core protein. Nef is CC probably cleaved concomitantly with viral structural proteins on CC maturation of virus particles. CC -!- PTM: Myristoylated. CC -!- PTM: Phosphorylated on serine residues, probably by host PKCdelta and CC theta. CC -!- MISCELLANEOUS: HIV-1 lineages are divided in three main groups, M (for CC Major), O (for Outlier), and N (for New, or Non-M, Non-O). The vast CC majority of strains found worldwide belong to the group M. Group O CC seems to be endemic to and largely confined to Cameroon and neighboring CC countries in West Central Africa, where these viruses represent a small CC minority of HIV-1 strains. The group N is represented by a limited CC number of isolates from Cameroonian persons. The group M is further CC subdivided in 9 clades or subtypes (A to D, F to H, J and K). CC -!- SIMILARITY: Belongs to the lentivirus primate group Nef protein family. XX DR Pfam; PF00469; F-protein; 1; trigger=no XX KW Apoptosis KW Early protein KW Host cell membrane KW Host Golgi apparatus KW Host membrane KW Host-virus interaction KW Inhibition of host adaptive immune response by virus KW Inhibition of host autophagy by virus KW Inhibition of host MHC class I molecule presentation by virus KW Inhibition of host MHC class II molecule presentation by virus KW Lipoprotein KW Membrane KW Myristate KW Phosphoprotein KW Secreted KW SH3-binding KW Viral immunoevasion KW Virion KW Virulence XX GO GO:0044178; C:host cell Golgi membrane GO GO:0020002; C:host cell plasma membrane GO GO:0016020; C:membrane GO GO:0044423; C:virion component GO GO:0005525; F:GTP binding GO GO:0017124; F:SH3 domain binding GO GO:0039504; P:suppression by virus of host adaptive immune response GO GO:0046776; P:suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I GO GO:0039505; P:suppression by virus of host antigen processing and presentation of peptide antigen via MHC class II GO GO:0039521; P:suppression by virus of host autophagy XX FT From: NEF_HV1H2 (P04601) FT INIT_MET Nter FT /note="Removed; by host" FT Condition: M FT CHAIN Nter+1..Cter FT /note="Protein Nef" FT CHAIN 58..Cter FT /note="C-terminal core protein" FT REGION 62..65 FT /note="Acidic; interacts with host PACS1 and PACS2; FT stabilizes the interaction of NEF/MHC-I with host AP1M1; FT necessary for MHC-I internalization" FT REGION 69..78 FT /note="SH3-binding; interaction with Src family tyrosine FT kinases" FT REGION 108..124 FT /note="Mediates dimerization, Nef-PTE1 interaction" FT REGION 148..180 FT /note="Binding to ATP6V1H" FT MOTIF 72..75 FT /note="PxxP; stabilizes the interaction of NEF/MHC-I with FT host AP1M1; necessary for MHC-I internalization" FT Condition: P-x(2)-P FT MOTIF 164..165 FT /note="Dileucine internalization motif; necessary for CD4 FT internalization" FT Condition: L-L FT MOTIF 174..175 FT /note="Diacidic; necessary for CD4 internalization" FT Condition: [ED]-D FT SITE 20 FT /note="Might play a role in AP-1 recruitment to the Nef- FT MHC-I complex" FT Condition: M FT SITE 57..58 FT /note="Cleavage; by viral protease" FT Condition: [FW]-L FT MOD_RES 6 FT /note="Phosphoserine; by host" FT Condition: S FT LIPID 2 FT /note="N-myristoyl glycine; by host" FT Condition: G XX Size: 200-239; Related: None; Template: P04601; Scope: Viruses; Lentivirus Fusion: Nter: None Cter: None Duplicate: None Plasmid: None Comments: None XX # Revision 1.7 2021/10/18 //