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 PancinoDavid M. Ojcius, Eric Solary, Eric Deutsch, Mauro Piacentini, Marie Lise Gougeon, Guido Kroemer, Jean Luc Perfettini

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)3381-3394.e7
Number of pages21
JournalCell Reports
Volume28
Issue number13
DOIs
Publication statusPublished - Sep 24 2019

Keywords

  • CBL
  • HIV
  • inflammasome
  • NLRP3
  • P2Y2
  • viral entry

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Paoletti, A., Allouch, A., Caillet, M., Saïdi, H., Subra, F., Nardacci, R., Wu, Q., Muradova, Z., Voisin, L., Raza, S. Q., Law, F., Thoreau, M., Dakhli, H., Delelis, O., Poirier-Beaudouin, B., Dereuddre-Bosquet, N., Le Grand, R., Lambotte, O., Saez-Cirion, A., ... Perfettini, J. L. (2019). HIV-1 Envelope Overcomes NLRP3-Mediated Inhibition of F-Actin Polymerization for Viral Entry. Cell Reports, 28(13), 3381-3394.e7. https://doi.org/10.1016/j.celrep.2019.02.095