title: Newly discovered viral E3 ligase pK3 induces endoplasmic reticulum-associated degradation of class I major histocompatibility proteins and their membrane-bound chaperones.
abstract: Viral immune invasion proteins are highly effective probes for studying physiological pathways. We report here the characterization of a new viral ubiquitin ligase pK3 expressed by rodent herpesvirus Peru (RHVP) that establishes acute and latent infection in laboratory mice. Our findings show that pK3 binds directly and specifically to class I major histocompatibility proteins (MHCI) in a transmembrane-dependent manner. This binding results in the rapid degradation of the pK3/MHCI complex by a mechanism dependent upon catalytically active pK3. Subsequently, the rapid degradation of pK3/MHCI secondarily causes the slow degradation of membrane bound components of the MHCI peptide loading complex, tapasin, and transporter associated with antigen processing (TAP). Interestingly, this secondary event occurs by cellular endoplasmic reticulum-associated degradation. Cumulatively, our findings show pK3 uses a unique mechanism of substrate detection and degradation compared with other viral or cellular E3 ligases. More importantly, our findings reveal that in the absence of nascent MHCI proteins in the endoplasmic reticulum, the transmembrane proteins TAP and tapasin that facilitate peptide binding to MHCI proteins are degraded by cellular quality control mechanisms.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Herr
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wang
authors.forename: Joy
authors.initials: J
authors.lastname: Loh
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.forename: Ted H
authors.initials: TH
authors.lastname: Hansen
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D006564:Herpesviridae / Q000201:enzymology* / Q000235:genetics; D006566:Herpesviridae Infections / Q000201:enzymology / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; D015395:Histocompatibility Antigens Class I; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases