4p6z

Structural highlights

Disease

[AP1S1_HUMAN] MEDNIK syndrome. The disease is caused by mutations affecting the gene represented in this entry.

Function

[BST2_HUMAN] IFN-induced antiviral host restriction factor which efficiently blocks the release of diverse mammalian enveloped viruses by directly tethering nascent virions to the membranes of infected cells. Acts as a direct physical tether, holding virions to the cell membrane and linking virions to each other. The tethered virions can be internalized by endocytosis and subsequently degraded or they can remain on the cell surface. In either case, their spread as cell-free virions is restricted. Its target viruses belong to diverse families, including retroviridae: human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), simian immunodeficiency viruses (SIVs), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), prototype foamy virus (PFV), Mason-Pfizer monkey virus (MPMV), human T-cell leukemia virus type 1 (HTLV-1), Rous sarcoma virus (RSV) and murine leukemia virus (MLV), flavivirideae: hepatitis C virus (HCV), filoviridae: ebola virus (EBOV) and marburg virus (MARV), arenaviridae: lassa virus (LASV) and machupo virus (MACV), herpesviridae: kaposis sarcoma-associated herpesvirus (KSHV), rhabdoviridae: vesicular stomatitis virus (VSV), orthomyxoviridae: influenza A virus, and paramyxoviridae: nipah virus. Can inhibit cell surface proteolytic activity of MMP14 causing decreased activation of MMP15 which results in inhibition of cell growth and migration. Can stimulate signaling by LILRA4/ILT7 and consequently provide negative feedback to the production of IFN by plasmacytoid dendritic cells in response to viral infection. Plays a role in the organization of the subapical actin cytoskeleton in polarized epithelial cells.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]} [AP1B1_HUMAN] Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. [AP1G1_MOUSE] Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. [AP1M1_MOUSE] Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the trans-Golgi network (TGN) and endosomes. The AP complexes mediate the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules. [AP1S1_HUMAN] Subunit of clathrin-associated adaptor protein complex 1 that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes. The AP complexes mediate both the recruitment of clathrin to membranes and the recognition of sorting signals within the cytosolic tails of transmembrane cargo molecules.^[16] [VPU_HV1S1] Enhances virion budding, by targeting human CD4 and Tetherin/BST2 to proteasome degradation. Degradation of CD4 prevents any unwanted premature interactions between viral Env and its receptor human CD4 in the endoplasmic reticulum. Degradation of antiretroviral protein Tetherin/BST2 is important for virion budding, as BST2 tethers new viral particles to the host cell membrane. Mechanistically, Vpu bridges either CD4 or BST2 to BTRC, a substrate recognition subunit of the Skp1/Cullin/F-box protein E3 ubiquitin ligase, induces their ubiquitination and subsequent proteasomal degradation. The alteration of the E3 ligase specificity by Vpu seems to interfere with the degradation of host IKBKB, leading to NF-kappa-B down-regulation and subsequent apoptosis. Ion channel activity has also been suggested, however, formation of cation-selective channel has been reconstituted ex-vivo in lipid bilayers. It is thus unsure that this activity plays a role in vivo (By similarity).

References

1. ↑ Van Damme N, Goff D, Katsura C, Jorgenson RL, Mitchell R, Johnson MC, Stephens EB, Guatelli J. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe. 2008 Apr 17;3(4):245-52. doi: 10.1016/j.chom.2008.03.001. Epub, 2008 Mar 13. PMID:18342597 doi:10.1016/j.chom.2008.03.001
2. ↑ Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature. 2008 Jan 24;451(7177):425-30. doi: 10.1038/nature06553. Epub 2008 Jan 16. PMID:18200009 doi:10.1038/nature06553
3. ↑ Perez-Caballero D, Zang T, Ebrahimi A, McNatt MW, Gregory DA, Johnson MC, Bieniasz PD. Tetherin inhibits HIV-1 release by directly tethering virions to cells. Cell. 2009 Oct 30;139(3):499-511. doi: 10.1016/j.cell.2009.08.039. PMID:19879838 doi:10.1016/j.cell.2009.08.039
4. ↑ Cao W, Bover L, Cho M, Wen X, Hanabuchi S, Bao M, Rosen DB, Wang YH, Shaw JL, Du Q, Li C, Arai N, Yao Z, Lanier LL, Liu YJ. Regulation of TLR7/9 responses in plasmacytoid dendritic cells by BST2 and ILT7 receptor interaction. J Exp Med. 2009 Jul 6;206(7):1603-14. doi: 10.1084/jem.20090547. Epub 2009 Jun, 29. PMID:19564354 doi:10.1084/jem.20090547
5. ↑ Jouvenet N, Neil SJ, Zhadina M, Zang T, Kratovac Z, Lee Y, McNatt M, Hatziioannou T, Bieniasz PD. Broad-spectrum inhibition of retroviral and filoviral particle release by tetherin. J Virol. 2009 Feb;83(4):1837-44. doi: 10.1128/JVI.02211-08. Epub 2008 Nov 26. PMID:19036818 doi:10.1128/JVI.02211-08
6. ↑ Kaletsky RL, Francica JR, Agrawal-Gamse C, Bates P. Tetherin-mediated restriction of filovirus budding is antagonized by the Ebola glycoprotein. Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2886-91. doi:, 10.1073/pnas.0811014106. Epub 2009 Jan 28. PMID:19179289 doi:10.1073/pnas.0811014106
7. ↑ Radoshitzky SR, Dong L, Chi X, Clester JC, Retterer C, Spurgers K, Kuhn JH, Sandwick S, Ruthel G, Kota K, Boltz D, Warren T, Kranzusch PJ, Whelan SP, Bavari S. Infectious Lassa virus, but not filoviruses, is restricted by BST-2/tetherin. J Virol. 2010 Oct;84(20):10569-80. doi: 10.1128/JVI.00103-10. Epub 2010 Aug 4. PMID:20686043 doi:10.1128/JVI.00103-10
8. ↑ Weidner JM, Jiang D, Pan XB, Chang J, Block TM, Guo JT. Interferon-induced cell membrane proteins, IFITM3 and tetherin, inhibit vesicular stomatitis virus infection via distinct mechanisms. J Virol. 2010 Dec;84(24):12646-57. doi: 10.1128/JVI.01328-10. Epub 2010 Oct 13. PMID:20943977 doi:10.1128/JVI.01328-10
9. ↑ Pardieu C, Vigan R, Wilson SJ, Calvi A, Zang T, Bieniasz P, Kellam P, Towers GJ, Neil SJ. The RING-CH ligase K5 antagonizes restriction of KSHV and HIV-1 particle release by mediating ubiquitin-dependent endosomal degradation of tetherin. PLoS Pathog. 2010 Apr 15;6(4):e1000843. doi: 10.1371/journal.ppat.1000843. PMID:20419159 doi:10.1371/journal.ppat.1000843
10. ↑ Xu F, Tan J, Liu R, Xu D, Li Y, Geng Y, Liang C, Qiao W. Tetherin inhibits prototypic foamy virus release. Virol J. 2011 May 2;8:198. doi: 10.1186/1743-422X-8-198. PMID:21529378 doi:10.1186/1743-422X-8-198
11. ↑ Watanabe R, Leser GP, Lamb RA. Influenza virus is not restricted by tetherin whereas influenza VLP production is restricted by tetherin. Virology. 2011 Aug 15;417(1):50-6. doi: 10.1016/j.virol.2011.05.006. Epub 2011, May 28. PMID:21621240 doi:10.1016/j.virol.2011.05.006
12. ↑ Gu G, Zhao D, Yin Z, Liu P. BST-2 binding with cellular MT1-MMP blocks cell growth and migration via decreasing MMP2 activity. J Cell Biochem. 2012 Mar;113(3):1013-21. doi: 10.1002/jcb.23433. PMID:22065321 doi:10.1002/jcb.23433
13. ↑ Dafa-Berger A, Kuzmina A, Fassler M, Yitzhak-Asraf H, Shemer-Avni Y, Taube R. Modulation of hepatitis C virus release by the interferon-induced protein BST-2/tetherin. Virology. 2012 Jul 5;428(2):98-111. doi: 10.1016/j.virol.2012.03.011. Epub 2012, Apr 20. PMID:22520941 doi:10.1016/j.virol.2012.03.011
14. ↑ Hinz A, Miguet N, Natrajan G, Usami Y, Yamanaka H, Renesto P, Hartlieb B, McCarthy AA, Simorre JP, Gottlinger H, Weissenhorn W. Structural basis of HIV-1 tethering to membranes by the BST-2/tetherin ectodomain. Cell Host Microbe. 2010 Apr 22;7(4):314-23. PMID:20399176 doi:10.1016/j.chom.2010.03.005
15. ↑ Yang H, Wang J, Jia X, McNatt MW, Zang T, Pan B, Meng W, Wang HW, Bieniasz PD, Xiong Y. Structural insight into the mechanisms of enveloped virus tethering by tetherin. Proc Natl Acad Sci U S A. 2010 Oct 12. PMID:20940320 doi:10.1073/pnas.1011485107
16. ↑ Takatsu H, Sakurai M, Shin HW, Murakami K, Nakayama K. Identification and characterization of novel clathrin adaptor-related proteins. J Biol Chem. 1998 Sep 18;273(38):24693-700. PMID:9733768