The herpesvirus UL49.5 protein hijacks a cellular C- degron pathway to drive TAP transporter degradation

• 成果类型: Article
• 署名作者: Wachalska, Magda; Riepe, Celeste; Slusarz, Magdalena J.; Graul, Malgorzata; Borowski, Lukasz S.; Qiao, Wenjie; Foltynska, Michalina; Carette, Jan E.; Szewczyk, Krystyna Bienkowska-; Szczesny, Roman J.; Kopito, Ron R.; Lipinska, Andrea D.
• 署名单位: Fahrenheit Universities; University of Gdansk; Fahrenheit Universities; Medical University Gdansk; Stanford University; Fahrenheit Universities; University of Gdansk; University of Warsaw; Stanford University; Polish Academy of Sciences; Institute of Biochemistry & Biophysics - Polish Academy of Sciences
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13976
• DOI: 10.1073/pnas.2309841121
• 发表日期: 2024-03-12
• 关键词: class-i molecules; e3 ligase; proteasomal degradation; aaa-atpase; ubiquitin; complex; RECOGNITION; inhibitor; binding

摘要

The transporter associated with antigen processing (TAP) is a key player in the major histocompatibility class I- restricted antigen presentation and an attractive target for immune evasion by viruses. Bovine herpesvirus 1 impairs TAP- dependent antigenic peptide transport through a two- pronged mechanism in which binding of the UL49.5 gene product to TAP both inhibits peptide transport and triggers its proteasomal degradation. How UL49.5 promotes TAP degradation has, so far, remained unknown. Here, we use high- content siRNA and genome-wide CRISPR-Cas9 screening to identify CLR2KLHDC3 as the E3 ligase responsible for UL49.5- triggered TAP disposal. We propose that the C terminus of UL49.5 mimics a C-end rule degron that recruits the E3 to TAP and engages the cullin-RING E3 ligase in endoplasmic reticulum- associated degradation.