Multiple E2 ubiquitin-conjugating enzymes regulate human cytomegalovirus US2-mediated immunoreceptor downregulation.

Abstract

Misfolded endoplasmic reticulum (ER) proteins are dislocated towards the cytosol and degraded by the ubiquitin-proteasome system in a process called ER-associated protein degradation (ERAD). During infection with human cytomegalovirus (HCMV), the viral US2 protein targets HLA class I molecules (HLA-I) for degradation via ERAD to avoid elimination by the immune system. US2-mediated degradation of HLA-I serves as a paradigm of ERAD and has facilitated the identification of TRC8 (also known as RNF139) as an E3 ubiquitin ligase. No specific E2 enzymes had previously been described for cooperation with TRC8. In this study, we used a lentiviral CRISPR/Cas9 library targeting all known human E2 enzymes to assess their involvement in US2-mediated HLA-I downregulation. We identified multiple E2 enzymes involved in this process, of which UBE2G2 was crucial for the degradation of various immunoreceptors. UBE2J2, on the other hand, counteracted US2-induced ERAD by downregulating TRC8 expression. These findings indicate the complexity of cellular quality control mechanisms, which are elegantly exploited by HCMV to elude the immune system.

• Authors: Michael L van de Weijer, Anouk B C Schuren, Dick J H van den Boomen, Arend Mulder, Frans H J Claas, Paul J Lehner, Robert Jan Lebbink, Emmanuel J H J Wiertz
• Journal: Journal of cell science (J Cell Sci) Vol. 130 Issue 17 Pg. 2883-2892 (Sep 01 2017) ISSN: 1477-9137 [Electronic] England
• PMID: 28743740 (Publication Type: Journal Article)
• Copyright: © 2017. Published by The Company of Biologists Ltd.

Chemical References

• Histocompatibility Antigens Class I
• RNF139 protein, human
• Receptors, Cell Surface
• Receptors, Immunologic
• US2 protein, Varicellovirus
• Viral Envelope Proteins
• UBE2G2 protein, human
• UBE2J2 protein, human
• Ubiquitin-Conjugating Enzymes

Topics

• CRISPR-Cas Systems (genetics)
• Cytomegalovirus (metabolism)
• Down-Regulation
• Genetic Testing
• Histocompatibility Antigens Class I (metabolism)
• Humans
• Models, Biological
• Proteolysis
• Receptors, Cell Surface (metabolism)
• Receptors, Immunologic (metabolism)
• U937 Cells
• Ubiquitin-Conjugating Enzymes (metabolism)
• Up-Regulation
• Viral Envelope Proteins (metabolism)