Adenovirus E1A Binding to DCAF10 Targets Degradation of AAA+ ATPases Required for Quaternary Assembly of Multiprotein Machines and Innate Immunity
bioRxiv (Cold Spring Harbor Laboratory)(2020)
摘要
Adenovirus E1A early proteins modify host cell physiology to optimize virus replication. The Nterminal half of small e1a interacts with RB-family proteins to de-repress dNTP and DNA synthesis, and with p300/CBP to inhibit host anti-viral innate immune responses. These e1a Nterminal interactions activate a strong, late host anti-viral response due to stabilization and activation of interferon response factor 3 (IRF3). However, the C-terminal half of e1a inhibits this through interactions with three host proteins with seemingly unrelated functions. Proteomic analysis showed that all three C-terminal interactions are required for e1a-association into an ~1 MDa multi-protein complex with scaffold subunits of a CRL4 E3 ubiquitin ligase and DCAF10, a presumed specificity subunit. This e1a-DCAF10-CRL4 prevents IRF3 stabilization indirectly by directing degradation of the essential AAA+ ATPases RUVBL1/2, subunits of several HSP90 co-chaperones required for quaternary assembly of cellular protein machines required for anti-viral defenses and responses to genotoxic and metabolic stress.
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关键词
innate immunity,multiprotein machines
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