ATG5 Selectively Engages Virus-tethered BST2/tetherin in an LC3C-associated Pathway

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2023 May 8

PMID 37155854

Authors

Delphine Judith

Margaux Versapuech

Fabienne Bejjani

Marjory Palaric

Pauline Verlhac

Aurelia Kuster

Leslie Lepont

Sarah Gallois-Montbrun

Katy Janvier

Clarisse Berlioz-Torrent

Affiliations

Soon will be listed here.

Abstract

Bone marrow stromal antigen 2 (BST2)/tetherin is a restriction factor that reduces HIV-1 dissemination by tethering virus at the cell surface. BST2 also acts as a sensor of HIV-1 budding, establishing a cellular antiviral state. The HIV-1 Vpu protein antagonizes BST2 antiviral functions via multiple mechanisms, including the subversion of an LC3C-associated pathway, a key cell intrinsic antimicrobial mechanism. Here, we describe the first step of this viral-induced LC3C-associated process. This process is initiated at the plasma membrane through the recognition and internalization of virus-tethered BST2 by ATG5, an autophagy protein. ATG5 and BST2 assemble as a complex, independently of the viral protein Vpu and ahead of the recruitment of the ATG protein LC3C. The conjugation of ATG5 with ATG12 is dispensable for this interaction. ATG5 recognizes cysteine-linked homodimerized BST2 and specifically engages phosphorylated BST2 tethering viruses at the plasma membrane, in an LC3C-associated pathway. We also found that this LC3C-associated pathway is used by Vpu to attenuate the inflammatory responses mediated by virion retention. Overall, we highlight that by targeting BST2 tethering viruses, ATG5 acts as a signaling scaffold to trigger an LC3C-associated pathway induced by HIV-1 infection.

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