ID VPU_HV1H2 Reviewed; 82 AA. AC P05919; Q9WB91; DT 01-NOV-1988, integrated into UniProtKB/Swiss-Prot. DT 13-SEP-2023, sequence version 2. DT 27-MAR-2024, entry version 141. DE RecName: Full=Protein Vpu {ECO:0000255|HAMAP-Rule:MF_04082}; DE AltName: Full=U ORF protein {ECO:0000255|HAMAP-Rule:MF_04082}; DE AltName: Full=Viral protein U {ECO:0000255|HAMAP-Rule:MF_04082}; GN Name=vpu {ECO:0000255|HAMAP-Rule:MF_04082}; OS Human immunodeficiency virus type 1 group M subtype B (isolate HXB2) OS (HIV-1). OC Viruses; Riboviria; Pararnavirae; Artverviricota; Revtraviricetes; OC Ortervirales; Retroviridae; Orthoretrovirinae; Lentivirus; OC Human immunodeficiency virus 1. OX NCBI_TaxID=11706; OH NCBI_TaxID=9606; Homo sapiens (Human). RN [1] RP NUCLEOTIDE SEQUENCE [GENOMIC RNA]. RX PubMed=3040055; DOI=10.1089/aid.1987.3.57; RA Ratner L., Fisher A., Jagodzinski L.L., Mitsuya H., Liou R.-S., Gallo R.C., RA Wong-Staal F.; RT "Complete nucleotide sequences of functional clones of the AIDS virus."; RL AIDS Res. Hum. Retroviruses 3:57-69(1987). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Chappey C.; RL Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases. RN [3] RP TOPOLOGY, SUBUNIT, AND SUBCELLULAR LOCATION. RX PubMed=8331740; DOI=10.1128/jvi.67.8.5056-5061.1993; RA Maldarelli F., Chen M.Y., Willey R.L., Strebel K.; RT "Human immunodeficiency virus type 1 Vpu protein is an oligomeric type I RT integral membrane protein."; RL J. Virol. 67:5056-5061(1993). RN [4] RP PHOSPHORYLATION AT SER-53 AND SER-57. RX PubMed=8107101; DOI=10.1006/jmbi.1994.1114; RA Schubert U., Henklein P., Boldyreff B., Wingender E., Strebel K., RA Porstmann T.; RT "The human immunodeficiency virus type 1 encoded Vpu protein is RT phosphorylated by casein kinase-2 (CK-2) at positions Ser52 and Ser56 RT within a predicted alpha-helix-turn-alpha-helix-motif."; RL J. Mol. Biol. 236:16-25(1994). RN [5] RP INTERACTION WITH HOST CD4. RX PubMed=7853484; DOI=10.1128/jvi.69.3.1510-1520.1995; RA Bour S., Schubert U., Strebel K.; RT "The human immunodeficiency virus type 1 Vpu protein specifically binds to RT the cytoplasmic domain of CD4: implications for the mechanism of RT degradation."; RL J. Virol. 69:1510-1520(1995). RN [6] RP FUNCTION. RX PubMed=8794357; DOI=10.1128/jvi.70.10.7108-7115.1996; RA Ewart G.D., Sutherland T., Gage P.W., Cox G.B.; RT "The Vpu protein of human immunodeficiency virus type 1 forms cation- RT selective ion channels."; RL J. Virol. 70:7108-7115(1996). RN [7] RP INTERACTION WITH HOST BTRC. RX PubMed=9660940; DOI=10.1016/s1097-2765(00)80056-8; RA Margottin F., Bour S.P., Durand H., Selig L., Benichou S., Richard V., RA Thomas D., Strebel K., Benarous R.; RT "A novel human WD protein, h-beta TrCp, that interacts with HIV-1 Vpu RT connects CD4 to the ER degradation pathway through an F-box motif."; RL Mol. Cell 1:565-574(1998). RN [8] RP FUNCTION. RX PubMed=11696595; DOI=10.1084/jem.194.9.1299; RA Akari H., Bour S., Kao S., Adachi A., Strebel K.; RT "The human immunodeficiency virus type 1 accessory protein Vpu induces RT apoptosis by suppressing the nuclear factor kappaB-dependent expression of RT antiapoptotic factors."; RL J. Exp. Med. 194:1299-1311(2001). RN [9] RP FUNCTION, AND INTERACTION WITH HOST FBXW11. RX PubMed=19730691; DOI=10.1371/journal.ppat.1000574; RA Mangeat B., Gers-Huber G., Lehmann M., Zufferey M., Luban J., Piguet V.; RT "HIV-1 Vpu neutralizes the antiviral factor Tetherin/BST-2 by binding it RT and directing its beta-TrCP2-dependent degradation."; RL PLoS Pathog. 5:E1000574-E1000574(2009). RN [10] RP FUNCTION, AND INTERACTION WITH HOST BST2. RX PubMed=19837671; DOI=10.1074/jbc.m109.058305; RA Iwabu Y., Fujita H., Kinomoto M., Kaneko K., Ishizaka Y., Tanaka Y., RA Sata T., Tokunaga K.; RT "HIV-1 accessory protein Vpu internalizes cell-surface BST-2/tetherin RT through transmembrane interactions leading to lysosomes."; RL J. Biol. Chem. 284:35060-35072(2009). RN [11] RP SUBUNIT. RX PubMed=24223193; DOI=10.1371/journal.pone.0079779; RA Padhi S., Khan N., Jameel S., Priyakumar U.D.; RT "Molecular dynamics simulations reveal the HIV-1 Vpu transmembrane protein RT to form stable pentamers."; RL PLoS ONE 8:E79779-E79779(2013). RN [12] RP REVIEW. RX PubMed=24822052; DOI=10.3389/fmicb.2014.00177; RA Roy N., Pacini G., Berlioz-Torrent C., Janvier K.; RT "Mechanisms underlying HIV-1 Vpu-mediated viral egress."; RL Front. Microbiol. 5:177-177(2014). RN [13] RP FUNCTION, AND INTERACTION WITH HOST AP1M1. RX PubMed=24843023; DOI=10.7554/elife.02362; RA Jia X., Weber E., Tokarev A., Lewinski M., Rizk M., Suarez M., Guatelli J., RA Xiong Y.; RT "Structural basis of HIV-1 Vpu-mediated BST2 antagonism via hijacking of RT the clathrin adaptor protein complex 1."; RL Elife 3:E02362-E02362(2014). RN [14] RP FUNCTION. RX PubMed=24498878; DOI=10.1186/1742-4690-11-15; RA Pham T.N., Lukhele S., Hajjar F., Routy J.P., Cohen E.A.; RT "HIV Nef and Vpu protect HIV-infected CD4+ T cells from antibody-mediated RT cell lysis through down-modulation of CD4 and BST2."; RL Retrovirology 11:15-15(2014). RN [15] RP FUNCTION, AND INTERACTION WITH HOST RANBP2. RX PubMed=32690953; DOI=10.1038/s41564-020-0753-6; RA Volcic M., Sparrer K.M.J., Koepke L., Hotter D., Sauter D., Stuerzel C.M., RA Scherer M., Stamminger T., Hofmann T.G., Arhel N.J., Wiesmueller L., RA Kirchhoff F.; RT "Vpu modulates DNA repair to suppress innate sensing and hyper-integration RT of HIV-1."; RL Nat. Microbiol. 5:1247-1261(2020). RN [16] RP SUBUNIT. RX PubMed=36796461; DOI=10.1016/j.jsb.2023.107943; RA Majeed S., Adetuyi O., Borbat P.P., Majharul Islam M., Ishola O., Zhao B., RA Georgieva E.R.; RT "Insights into the oligomeric structure of the HIV-1 Vpu protein."; RL J. Struct. Biol. 215:107943-107943(2023). RN [17] {ECO:0007744|PDB:2N29} RP STRUCTURE BY NMR OF 29-82, AND DOMAIN. RX PubMed=26362058; DOI=10.1016/j.bbamem.2015.09.008; RA Zhang H., Lin E.C., Das B.B., Tian Y., Opella S.J.; RT "Structural determination of virus protein U from HIV-1 by NMR in membrane RT environments."; RL Biochim. Biophys. Acta 1848:3007-3018(2015). CC -!- FUNCTION: Enhances virion budding by targeting host CD4 and CC Tetherin/BST2 to proteasome degradation. Degradation of CD4 prevents CC any unwanted premature interactions between viral Env and its host CC receptor CD4 in the endoplasmic reticulum. Degradation of CC antiretroviral protein Tetherin/BST2 is important for virion budding, CC as BST2 tethers new viral particles to the host cell membrane. CC Mechanistically, Vpu bridges either CD4 or BST2 to BTRC, a substrate CC recognition subunit of the Skp1/Cullin/F-box protein E3 ubiquitin CC ligase, induces their ubiquitination and subsequent proteasomal CC degradation. The alteration of the E3 ligase specificity by Vpu seems CC to promote the degradation of host IKBKB, leading to NF-kappa-B down- CC regulation and subsequent apoptosis. Acts as a viroporin that forms an CC oligomeric ion channel in membranes. Modulates the host DNA repair CC mechanisms to promote degradation of nuclear viral cDNA in cells that CC are already productively infected in order to suppress immune sensing CC and proviral hyper-integration (superinfection). Manipulates PML-NBs CC and modulates SUMOylation of host BLM protein thereby enhancing its CC DNA-end processing activity toward viral unintegrated linear DNA. Also CC inhibits RAD52-mediated homologous repair of viral cDNA, preventing the CC generation of dead-end circular forms of single copies of the long CC terminal repeat and permitting sustained nucleolytic attack. CC {ECO:0000255|HAMAP-Rule:MF_04082, ECO:0000269|PubMed:11696595, CC ECO:0000269|PubMed:19730691, ECO:0000269|PubMed:19837671, CC ECO:0000269|PubMed:24498878, ECO:0000269|PubMed:24843023, CC ECO:0000269|PubMed:32690953, ECO:0000269|PubMed:8794357}. CC -!- ACTIVITY REGULATION: Ion channel activity is inhibited by hexamethylene CC amiloride in vitro. {ECO:0000255|HAMAP-Rule:MF_04082}. CC -!- SUBUNIT: Homopentamer (PubMed:36796461). Interacts with host CD4 and CC BRTC; these interactions induce proteasomal degradation of CD4. CC Interacts (via transmembrane region) with host BST2 (via transmembrane CC region); this interaction leads to the degradation of host BST2. CC Interacts with host FBXW11. Interacts with host AP1M1; this interaction CC plays a role in the mistrafficking and subsequent degradation of host CC BST2. Interacts with host RANBP2; this interaction allows Vpu to down- CC regulate host BLM sumoylation. {ECO:0000255|HAMAP-Rule:MF_04082, CC ECO:0000269|PubMed:19730691, ECO:0000269|PubMed:19837671, CC ECO:0000269|PubMed:24223193, ECO:0000269|PubMed:24843023, CC ECO:0000269|PubMed:32690953, ECO:0000269|PubMed:36796461, CC ECO:0000269|PubMed:7853484, ECO:0000269|PubMed:8331740, CC ECO:0000269|PubMed:9660940}. CC -!- INTERACTION: CC P05919; P01730: CD4; Xeno; NbExp=3; IntAct=EBI-6164626, EBI-353826; CC -!- SUBCELLULAR LOCATION: Host membrane {ECO:0000255|HAMAP-Rule:MF_04082}; CC Single-pass type I membrane protein {ECO:0000255|HAMAP-Rule:MF_04082, CC ECO:0000269|PubMed:8331740}. CC -!- DOMAIN: The N-terminus and transmembrane domains are required for self- CC oligomerization and proper virion budding, whereas the cytoplasmic CC domain is required for CD4 degradation. The cytoplasmic domain is CC composed of 2 amphipathic alpha helix that form a U-shape. CC {ECO:0000255|HAMAP-Rule:MF_04082, ECO:0000269|PubMed:26362058}. CC -!- PTM: Phosphorylated by host CK2. This phosphorylation is necessary for CC interaction with human BTRC and degradation of CD4. {ECO:0000255|HAMAP- CC Rule:MF_04082}. 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 {ECO:0000255|HAMAP-Rule:MF_04082}. CC -!- SIMILARITY: Belongs to the HIV-1 VPU protein family. CC {ECO:0000255|HAMAP-Rule:MF_04082}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; K03455; -; NOT_ANNOTATED_CDS; Genomic_RNA. DR EMBL; AF033819; AAD20388.1; -; Genomic_RNA. DR RefSeq; NP_057855.1; NC_001802.1. DR PDB; 2N29; NMR; -; A=29-82. DR PDBsum; 2N29; -. DR BMRB; P05919; -. DR SMR; P05919; -. DR IntAct; P05919; 55. DR TCDB; 1.A.40.1.1; the human immunodeficiency virus type i, hiv-1 (retrovirdiac) vpu channel (vpu-c) family. DR iPTMnet; P05919; -. DR GeneID; 155945; -. DR KEGG; vg:155945; -. DR Reactome; R-HSA-162585; Uncoating of the HIV Virion. DR Reactome; R-HSA-162588; Budding and maturation of HIV virion. DR Reactome; R-HSA-162592; Integration of provirus. DR Reactome; R-HSA-162594; Early Phase of HIV Life Cycle. DR Reactome; R-HSA-164516; Minus-strand DNA synthesis. DR Reactome; R-HSA-164525; Plus-strand DNA synthesis. DR Reactome; R-HSA-164843; 2-LTR circle formation. DR Reactome; R-HSA-171286; Synthesis and processing of ENV and VPU. DR Reactome; R-HSA-173107; Binding and entry of HIV virion. DR Reactome; R-HSA-175474; Assembly Of The HIV Virion. DR Reactome; R-HSA-175567; Integration of viral DNA into host genomic DNA. DR Reactome; R-HSA-177539; Autointegration results in viral DNA circles. DR Reactome; R-HSA-180534; Vpu mediated degradation of CD4. DR Reactome; R-HSA-180689; APOBEC3G mediated resistance to HIV-1 infection. DR Reactome; R-HSA-180910; Vpr-mediated nuclear import of PICs. DR Proteomes; UP000002241; Segment. DR Proteomes; UP000105453; Segment. DR GO; GO:0033644; C:host cell membrane; IEA:UniProtKB-SubCell. DR GO; GO:0016020; C:membrane; IEA:UniProtKB-UniRule. DR GO; GO:0042609; F:CD4 receptor binding; IEA:UniProtKB-UniRule. DR GO; GO:0005261; F:monoatomic cation channel activity; IEA:UniProtKB-UniRule. DR GO; GO:0032801; P:receptor catabolic process; IEA:UniProtKB-UniRule. DR GO; GO:0039587; P:suppression by virus of host tetherin activity; IEA:UniProtKB-UniRule. DR GO; GO:0039502; P:suppression by virus of host type I interferon-mediated signaling pathway; IEA:UniProtKB-UniRule. DR GO; GO:0019076; P:viral release from host cell; IEA:UniProtKB-UniRule. DR Gene3D; 1.10.195.10; HIV-1 VPU cytoplasmic domain; 1. DR HAMAP; MF_04082; HIV_VPU; 1. DR InterPro; IPR008187; Vpu. DR InterPro; IPR009032; Vpu_cyt_dom_sf. DR Pfam; PF00558; Vpu; 1. DR SUPFAM; SSF57647; HIV-1 VPU cytoplasmic domain; 1. PE 1: Evidence at protein level; KW 3D-structure; AIDS; Apoptosis; Host membrane; Host-virus interaction; KW Inhibition of host innate immune response by virus; KW Inhibition of host tetherin by virus; Ion channel; Ion transport; Membrane; KW Phosphoprotein; Reference proteome; Transmembrane; Transmembrane helix; KW Transport; Viral immunoevasion. FT CHAIN 1..82 FT /note="Protein Vpu" FT /id="PRO_0000085433" FT TOPO_DOM 1..7 FT /note="Extracellular" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04082" FT TRANSMEM 8..28 FT /note="Helical" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04082" FT TOPO_DOM 29..82 FT /note="Cytoplasmic" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04082" FT MOD_RES 53 FT /note="Phosphoserine; by host CK2" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04082, FT ECO:0000269|PubMed:8107101" FT MOD_RES 57 FT /note="Phosphoserine; by host CK2" FT /evidence="ECO:0000255|HAMAP-Rule:MF_04082, FT ECO:0000269|PubMed:8107101" FT HELIX 36..40 FT /evidence="ECO:0007829|PDB:2N29" FT HELIX 41..50 FT /evidence="ECO:0007829|PDB:2N29" FT HELIX 57..69 FT /evidence="ECO:0007829|PDB:2N29" FT TURN 73..76 FT /evidence="ECO:0007829|PDB:2N29" FT STRAND 77..79 FT /evidence="ECO:0007829|PDB:2N29" SQ SEQUENCE 82 AA; 9242 MW; 53D79E576ACAD7DA CRC64; MQPIPIVAIV ALVVAIIIAI VVWSIVIIEY RKILRQRKID RLIDRLIERA EDSGNESEGE ISALVEMGVE MGHHAPWDVD DL //