Cell Reports (Sep 2019)

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

  • Audrey Paoletti,
  • Awatef Allouch,
  • Marina Caillet,
  • Hela Saïdi,
  • Frédéric Subra,
  • Roberta Nardacci,
  • Qiuji Wu,
  • Zeinaf Muradova,
  • Laurent Voisin,
  • Syed Qasim Raza,
  • Frédéric Law,
  • Maxime Thoreau,
  • Haithem Dakhli,
  • Olivier Delelis,
  • Béatrice Poirier-Beaudouin,
  • Nathalie Dereuddre-Bosquet,
  • Roger Le Grand,
  • Olivier Lambotte,
  • Asier Saez-Cirion,
  • Gianfranco Pancino,
  • David M. Ojcius,
  • Eric Solary,
  • Eric Deutsch,
  • Mauro Piacentini,
  • Marie-Lise Gougeon,
  • Guido Kroemer,
  • Jean-Luc Perfettini

Journal volume & issue
Vol. 28, no. 13
pp. 3381 – 3394.e7

Abstract

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Summary: 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. : 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. Keywords: NLRP3, P2Y2, CBL, inflammasome, viral entry, HIV