HIV-1 Envelope Overcomes NLRP3-Mediated Inhibition of F-Actin Polymerization for Viral Entry

摘要

Purinergic receptors and nucleotide-binding domainleucine-rich repeat containing (NLR) proteins havebeen shown to control viral infection. Here, weshow that the NLR family member NLRP3 and thepurinergic receptor P2Y2 constitutively interact andregulate susceptibility to HIV-1 infection. We foundthat NLRP3 acts as an inhibitory factor of viral entrythat represses F-actin remodeling. The binding ofthe HIV-1 envelope to its host cell receptors (CD4,CXCR4, and/or CCR5) overcomes this restriction bystimulating P2Y2. Once activated, P2Y2 enhancesits interaction with NLRP3 and stimulates the recruitmentof the E3 ubiquitin ligase CBL to NLRP3,ultimately leading to NLRP3 degradation. NLRP3degradation is permissive for PYK2 phosphorylation(PYK2Y402*) and subsequent F-actin polymerization,which is required for the entry of HIV-1 intohost cells. Taken together, our results uncover amechanism by which HIV-1 overcomes NLRP3 restrictionthat appears essential for the accomplishmentof the early steps of HIV-1 entry.