Identifying the ERAD ubiquitin E3 ligases for viral and cellular targeting of MHC class I
van, den Boomen DJH
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van, d. B. D., & Lehner, P. (2015). Identifying the ERAD ubiquitin E3 ligases for viral and cellular targeting of MHC class I. Molecular Immunology, 68 106-111. https://doi.org/10.1016/j.molimm.2015.07.005
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.
ER-associated degradation, E3 ubiquitin ligase, Human cytomegalovirus, Viral immune evasion, TRC8, TMEM129, HRD1
This study was financially supported by the Wellcome Trust (084957/Z/08/Z) and the Cambridge Biomedical Research Centre, UK.
Wellcome Trust (101835/Z/13/Z)
Wellcome Trust (084957/Z/08/Z)
Wellcome Trust (100140/Z/12/Z)
External DOI: https://doi.org/10.1016/j.molimm.2015.07.005
This record's URL: https://www.repository.cam.ac.uk/handle/1810/249122
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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