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

• Published in: Cell reports (Cambridge) Vol. 28; no. 13; pp. 3381 - 3394.e7
• Main Authors: Paoletti, Audrey, Allouch, Awatef, Caillet, Marina, Saïdi, Hela, Subra, Frédéric, Nardacci, Roberta, Wu, Qiuji, Muradova, Zeinaf, Voisin, Laurent, Raza, Syed Qasim, Law, Frédéric, Thoreau, Maxime, Dakhli, Haithem, Delelis, Olivier, Poirier-Beaudouin, Béatrice, Dereuddre-Bosquet, Nathalie, Le Grand, Roger, Lambotte, Olivier, Saez-Cirion, Asier, Pancino, Gianfranco, Ojcius, David M., Solary, Eric, Deutsch, Eric, Piacentini, Mauro, Gougeon, Marie-Lise, Kroemer, Guido, Perfettini, Jean-Luc
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24-09-2019; Elsevier
• Subjects: CBL; Computer Science; Digital Libraries; HIV; inflammasome; Medicin och hälsovetenskap; NLRP3; P2Y2; viral entry; viral entry; NLRP3; HIV; CBL; inflammasome; P2Y2
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.02.095

Purinergic receptors and nucleotide-binding domain leucine-rich repeat containing (NLR) proteins have been shown to control viral infection. Here, we show that the NLR family member NLRP3 and the purinergic receptor P2Y2 constitutively interact and regulate susceptibility to HIV-1 infection. We found that NLRP3 acts as an inhibitory factor of viral entry that represses F-actin remodeling. The binding of the HIV-1 envelope to its host cell receptors (CD4, CXCR4, and/or CCR5) overcomes this restriction by stimulating P2Y2. Once activated, P2Y2 enhances its interaction with NLRP3 and stimulates the recruitment of the E3 ubiquitin ligase CBL to NLRP3, ultimately leading to NLRP3 degradation. NLRP3 degradation is permissive for PYK2 phosphorylation (PYK2Y402∗) and subsequent F-actin polymerization, which is required for the entry of HIV-1 into host cells. Taken together, our results uncover a mechanism by which HIV-1 overcomes NLRP3 restriction that appears essential for the accomplishment of the early steps of HIV-1 entry.
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•NLRP3 and P2Y2 interact and regulate susceptibility to HIV-1 infection•NLRP3 is an intrinsic inhibitory factor for HIV-1 that represses F-actin remodeling•HIV-1 Env binding to host receptors overcomes NLRP3 restriction by activating P2Y2•P2Y2 activation leads to CBL-mediated NLRP3 degradation and favors viral entry
Paoletti et al. identified a constitutive interaction between NLRP3 and P2Y2 that regulates HIV-1 entry into target cells. They revealed that NLRP3 represses viral entry by impairing F-actin reorganization. HIV-1 overcomes this host cellular resistance by inducing NLRP3 degradation through the activation of P2Y2-dependent signaling pathway.