Adenovirus E1A Binding to DCAF10 Targets Degradation of AAA+ ATPases Required for Quaternary Assembly of Multiprotein Machines and Innate Immunity

Abstract

Adenovirus E1A early proteins modify host cell physiology to optimize virus replication. The N-terminal 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 N-terminal 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.