2d8s

Structural highlights

Function

MARH8_HUMAN E3 ubiquitin-protein ligase that plays several important roles in innate immunity and adaptive immunity (PubMed:34285233, PubMed:35019698, PubMed:35503863). Mediates ubiquitination of CD86 and MHC class II proteins, such as HLA-DR alpha and beta, and promotes their subsequent endocytosis and sorting to lysosomes via multivesicular bodies (PubMed:19117940, PubMed:19566897). Possesses a very broad antiviral activity by specifically inactivating different viral fusion proteins (PubMed:32934085). Targets and ubiquitinates cytoplasmic lysine residues of viral envelope glycoproteins with single transmembrane domains leading to their lysosomal degradation (PubMed:35019698). Therefore, shows broad-spectrum inhibition against many viruses including retroviruses, rhabdoviruses, arenaviruses, sarbecoviruses or influenzaviruses (PubMed:34285233, PubMed:35019698). Strongly blocks human immunodeficiency virus type 1 envelope glycoprotein incorporation into virions by down-regulating its cell surface expression. Blocks also ebola virus glycoprotein/GP incorporation via surface down-regulation (PubMed:32934085). Mediates 'Lys-63'-linked polyubiquitination of influenza M2 to target it to lysosome for degradation (PubMed:34285233). Mediates the regulation of constitutive ubiquitination and trafficking of the viral restriction factor BST2 within the endocytic pathway (PubMed:28320822). Plays a role in maintenance of immune tolerance to self by promoting the turnover and proteasomal degradation of PD-L1/CD274 via ubiquitination (PubMed:34183449). Catalyzes the 'Lys-63'-linked polyubiquitylation of cGAS thereby inhibiting its DNA binding ability and impairing its antiviral innate immunity (PubMed:35503863).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]} (Microbial infection) Mediates 'Lys-63'-linked polyubiquitination of hepatitis C virus/HCV protein NS2 which allows its binding to HGS, an ESCRT-0 complex component, and this interaction is essential for HCV envelopment.^[12]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

References

1. ↑ Goto E, Ishido S, Sato Y, Ohgimoto S, Ohgimoto K, Nagano-Fujii M, Hotta H. c-MIR, a human E3 ubiquitin ligase, is a functional homolog of herpesvirus proteins MIR1 and MIR2 and has similar activity. J Biol Chem. 2003 Apr 25;278(17):14657-68. PMID:12582153 doi:10.1074/jbc.M211285200
2. ↑ Bartee E, Mansouri M, Hovey Nerenberg BT, Gouveia K, Früh K. Downregulation of major histocompatibility complex class I by human ubiquitin ligases related to viral immune evasion proteins. J Virol. 2004 Feb;78(3):1109-20. PMID:14722266 doi:10.1128/jvi.78.3.1109-1120.2004
3. ↑ Thibodeau J, Bourgeois-Daigneault MC, Huppé G, Tremblay J, Aumont A, Houde M, Bartee E, Brunet A, Gauvreau ME, de Gassart A, Gatti E, Baril M, Cloutier M, Bontron S, Früh K, Lamarre D, Steimle V. Interleukin-10-induced MARCH1 mediates intracellular sequestration of MHC class II in monocytes. Eur J Immunol. 2008 May;38(5):1225-30. PMID:18389477 doi:10.1002/eji.200737902
4. ↑ Lapaque N, Jahnke M, Trowsdale J, Kelly AP. The HLA-DRalpha chain is modified by polyubiquitination. J Biol Chem. 2009 Mar 13;284(11):7007-16. PMID:19117940 doi:10.1074/jbc.M805736200
5. ↑ Gauvreau ME, Côté MH, Bourgeois-Daigneault MC, Rivard LD, Xiu F, Brunet A, Shaw A, Steimle V, Thibodeau J. Sorting of MHC class II molecules into exosomes through a ubiquitin-independent pathway. Traffic. 2009 Oct;10(10):1518-27. PMID:19566897 doi:10.1111/j.1600-0854.2009.00948.x
6. ↑ Roy N, Pacini G, Berlioz-Torrent C, Janvier K. Characterization of E3 ligases involved in lysosomal sorting of the HIV-1 restriction factor BST2. J Cell Sci. 2017 May 1;130(9):1596-1611. PMID:28320822 doi:10.1242/jcs.195412
7. ↑ Yu C, Li S, Zhang X, Khan I, Ahmad I, Zhou Y, Li S, Shi J, Wang Y, Zheng YH. MARCH8 Inhibits Ebola Virus Glycoprotein, Human Immunodeficiency Virus Type 1 Envelope Glycoprotein, and Avian Influenza Virus H5N1 Hemagglutinin Maturation. mBio. 2020 Sep 15;11(5):e01882-20. PMID:32934085 doi:10.1128/mBio.01882-20
8. ↑ Qian G, Guo J, Vallega KA, Hu C, Chen Z, Deng Y, Wang Q, Fan S, Ramalingam SS, Owonikoko TK, Wei W, Sun SY. Membrane-Associated RING-CH 8 Functions as a Novel PD-L1 E3 Ligase to Mediate PD-L1 Degradation Induced by EGFR Inhibitors. Mol Cancer Res. 2021 Oct;19(10):1622-1634. PMID:34183449 doi:10.1158/1541-7786.MCR-21-0147
9. ↑ Liu X, Xu F, Ren L, Zhao F, Huang Y, Wei L, Wang Y, Wang C, Fan Z, Mei S, Song J, Zhao Z, Cen S, Liang C, Wang J, Guo F. MARCH8 inhibits influenza A virus infection by targeting viral M2 protein for ubiquitination-dependent degradation in lysosomes. Nat Commun. 2021 Jul 20;12(1):4427. PMID:34285233 doi:10.1038/s41467-021-24724-2
10. ↑ Zhang Y, Ozono S, Tada T, Tobiume M, Kameoka M, Kishigami S, Fujita H, Tokunaga K. MARCH8 Targets Cytoplasmic Lysine Residues of Various Viral Envelope Glycoproteins. Microbiol Spectr. 2022 Feb 23;10(1):e0061821. PMID:35019698 doi:10.1128/spectrum.00618-21
11. ↑ Yang X, Shi C, Li H, Shen S, Su C, Yin H. MARCH8 attenuates cGAS-mediated innate immune responses through ubiquitylation. Sci Signal. 2022 May 3;15(732):eabk3067. PMID:35503863 doi:10.1126/scisignal.abk3067
12. ↑ Kumar S, Barouch-Bentov R, Xiao F, Schor S, Pu S, Biquand E, Lu A, Lindenbach BD, Jacob Y, Demeret C, Einav S. MARCH8 Ubiquitinates the Hepatitis C Virus Nonstructural 2 Protein and Mediates Viral Envelopment. Cell Rep. 2019 Feb 12;26(7):1800-1814.e5. PMID:30759391 doi:10.1016/j.celrep.2019.01.075