Virome-wide ubiquitin ligase discovery reveals diverse mechanisms of immune evasion

• 成果类型: Article
• 署名作者: Glassman, Caleb R.; Baek, Kheewoong; Hou, Gaopeng; Zeng, Qiru; Nardone, Christopher; Juergens, Kate B.; Fujimura, Eric; O'Leary, Colin N.; Li, Mamie Z.; Paulo, Joao A.; Fischer, Eric S.; Ding, Siyuan; Harper, J. Wade; Elledge, Stephen J.
• 署名单位: Harvard University; Harvard Medical School; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Dana-Farber Cancer Institute; Harvard University; Harvard Medical School; Washington University (WUSTL); Saint Louis University; Harvard University; Harvard Medical School; Harvard University; Harvard Medical School; Harvard University; Harvard University; Harvard Medical School
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aec6299
• 发表日期: 2026-08-20
• 页码: eaec6299
• 关键词: F-BOX PROTEINS; KAPPA-B-ALPHA; structural basis; complex; virus; degradation; activation; infection; sequence; binding

摘要

Viruses are intracellular parasites that reprogram the host proteome to promote replication and evade immune recognition. We applied a virome-wide library of similar to 10,000 open reading frames to discover viral ubiquitin ligases, mapping their mechanisms of degradation and host substrates using targeted CRISPR screens and proteomics. These viral effectors could be classified as canonical ligases that mimic host E3s, hijackers that redirect host E3s, and noncanonical ligases that rewire cullin-RING ligase machinery. These diverse strategies of virus-mediated degradation converged on immune-related substrates, including JAK1 and CUL1 beta-TrCP, underscoring immune evasion as a major driver of viral ubiquitin ligase evolution. Our findings elucidate viral strategies for exploiting the ubiquitin-proteasome system with potential for therapeutic targeting.