The HIV-1 nucleocapsid regulates its own condensation by phase-separated activity-enhancing sequestration of the viral protease during maturation

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• dc.contributor.author Lyonnais, Sébastien
• dc.contributor.author Sadiq, S. Kashif
• dc.contributor.author Lorca Oró, Cristina
• dc.contributor.author Dufau, Laure
• dc.contributor.author Nieto-Marquez, Sara
• dc.contributor.author Escribà, Tuixent
• dc.contributor.author Gabrielli, Natalia, 1978-
• dc.contributor.author Tan, Xiao
• dc.contributor.author Ouizougun-Oubari, Mohamed
• dc.contributor.author Okoronkwo, Josephine
• dc.contributor.author Reboud-Ravaux, Michèle
• dc.contributor.author Gatell, Josep M.
• dc.contributor.author Marquet, Roland
• dc.contributor.author Paillart, Jean-Christophe
• dc.contributor.author Meyerhans, Andreas
• dc.contributor.author Tisné, Carine
• dc.contributor.author Gorelick, Robert J.
• dc.contributor.author Mirambeau, Gilles
• dc.date.accessioned 2022-02-02T07:30:18Z
• dc.date.available 2022-02-02T07:30:18Z
• dc.date.issued 2021
• dc.description.abstract
• dc.description.abstract A growing number of studies indicate that mRNAs and long ncRNAs can affect protein populations by assembling dynamic ribonucleoprotein (RNP) granules. These phase-separated molecular 'sponges', stabilized by quinary (transient and weak) interactions, control proteins involved in numerous biological functions. Retroviruses such as HIV-1 form by self-assembly when their genomic RNA (gRNA) traps Gag and GagPol polyprotein precursors. Infectivity requires extracellular budding of the particle followed by maturation, an ordered processing of ∼2400 Gag and ∼120 GagPol by the viral protease (PR). This leads to a condensed gRNA-NCp7 nucleocapsid and a CAp24-self-assembled capsid surrounding the RNP. The choreography by which all of these components dynamically interact during virus maturation is one of the missing milestones to fully depict the HIV life cycle. Here, we describe how HIV-1 has evolved a dynamic RNP granule with successive weak-strong-moderate quinary NC-gRNA networks during the sequential processing of the GagNC domain. We also reveal two palindromic RNA-binding triads on NC, KxxFxxQ and QxxFxxK, that provide quinary NC-gRNA interactions. Consequently, the nucleocapsid complex appears properly aggregated for capsid reassembly and reverse transcription, mandatory processes for viral infectivity. We show that PR is sequestered within this RNP and drives its maturation/condensation within minutes, this process being most effective at the end of budding. We anticipate such findings will stimulate further investigations of quinary interactions and emergent mechanisms in crowded environments throughout the wide and growing array of RNP granules.
• dc.description.sponsorship This work was supported in part by the European Project THINPAD “Targeting the HIV-1 Nucleocapsid Protein to fight Antiretroviral Drug Resistance” (FP7-Grant Agreement 601969), by Foundation Clinic, by ANRS, by SIDACTION, and with federal funds from the NCI/NIH, under Contract No. HHSN261200800001E with Leidos Biomedical Research, Inc. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government (R.J.G.). S.L. acknowledges funding by the Marie-Curie IEF fellowship (FP7-Grant Agreement 237738) and is grateful to Maria Solà (IBMB-CSIC). S.K.S. and A.M. acknowledge support from amfAR Mathilde Krim Fellowship in Basic Biomedical Research number 108680 and the Spanish Ministry of Economy and Competitiveness and FEDER (Grant no. SAF2013-46077-R). S.K.S. also gratefully acknowledges support from the Volkswagen Foundation “Experiment! Funding Initiative” grant number 93874 and from the Klaus Tschira Stiftung.
• dc.format.mimetype application/pdf
• dc.identifier.citation Lyonnais S, Sadiq SK, Lorca-Oró C, Dufau L, Nieto-Marquez S, Escribà T, Gabrielli N, Tan X, Ouizougun-Oubari M, Okoronkwo J, Reboud-Ravaux M, Gatell JM, Marquet R, Paillart JC, Meyerhans A, Tisné C, Gorelick RJ, Mirambeau G. The HIV-1 nucleocapsid regulates its own condensation by phase-separated activity-enhancing sequestration of the viral protease during maturation. Viruses. 2021;13(11):2312. DOI: 10.3390/v13112312
• dc.identifier.doi http://dx.doi.org/10.3390/v13112312
• dc.identifier.issn 1999-4915
• dc.identifier.uri http://hdl.handle.net/10230/52389
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Viruses. 2021;13(11):2312
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/601969
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/237738
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-46077-R
• dc.rights © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword HIV-1
• dc.subject.keyword RNA
• dc.subject.keyword Atomic-force microscopy
• dc.subject.keyword Biomolecular condensates
• dc.subject.keyword Enzyme catalysis
• dc.subject.keyword Liquid–liquid phase separation
• dc.subject.keyword Molecular dynamics
• dc.subject.keyword Nucleocapsid
• dc.subject.keyword Protease
• dc.title The HIV-1 nucleocapsid regulates its own condensation by phase-separated activity-enhancing sequestration of the viral protease during maturation
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion