title: Identifying the ERAD ubiquitin E3 ligases for viral and cellular targeting of MHC class I.
abstract: The human cytomegalovirus (HCMV) US2 and US11 gene products hijack mammalian ER-associated degradation (ERAD) to induce rapid degradation of major histocompatibility class I (MHC-I) molecules. The rate-limiting step in this pathway is thought to be the polyubiquitination of MHC-I by distinct host ERAD E3 ubiquitin ligases. TRC8 was identified as the ligase responsible for US2-mediated MHC-I degradation and shown to be required for the cleavage-dependent degradation of some tail-anchored proteins. In addition to MHC-I, plasma membrane profiling identified further immune receptors, which are also substrates for the US2/TRC8 complex. These include at least six α integrins, the coagulation factor thrombomodulin and the NK cell ligand CD112. US2's use of specific HCMV-encoded adaptors makes it an adaptable viral degradation hub. US11-mediated degradation is MHC-I-specific and genetic screens have identified TMEM129, an uncharacterised RING-C2 E3 ligase, as responsible for US11-mediated degradation. In a unique auto-regulatory loop, US11 readily responds to changes in cellular expression of MHC-I. Free US11 either rebinds more MHC-I or is itself degraded by the HRD1/SEL1L E3 ligase complex. While virally encoded US2 and US11 appropriate mammalian ERAD, the MHC-I complex also undergoes stringent cellular quality control and misfolded MHC-I is degraded by the HRD1/SEL1L complex. We discuss the identification and central role of E3 ubiquitin ligases in ER quality control and viral degradation of the MHC-I chain.
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address: djhv2@cam.ac.uk.
authors.forename: D J H
authors.initials: DJ
authors.lastname: van den Boomen
authors.affiliation: Cambridge Institute for Medical Research, Department of Medicine, University of Cambridge, Cambridge CB2 0XY, UK. Electronic address: pjl30@cam.ac.uk.
authors.forename: P J
authors.initials: PJ
authors.lastname: Lehner
mesh_terms: D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D060746:Endoplasmic Reticulum-Associated Degradation / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics / Q000276:immunology; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000276:immunology; D059748:Proteolysis; D016601:RNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D018180:Thrombomodulin / Q000235:genetics / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology; D054875:Ubiquitination; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D015395:Histocompatibility Antigens Class I; C508020:IL2RB protein, human; D039001:Integrin alpha Chains; D053646:Interleukin-2 Receptor beta Subunit; D016601:RNA-Binding Proteins; C114025:RNF139 protein, human; D011956:Receptors, Cell Surface; C546931:THBD protein, human; D018180:Thrombomodulin; C074546:US11 protein, herpesvirus; C118670:US2 protein, Varicellovirus; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C000591994:TMEM129 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: E3 ubiquitin ligase; ER-associated degradation; HRD1; Human cytomegalovirus; TMEM129; TRC8; Viral immune evasion