LC3C Contributes to Vpu-Mediated Antagonism of BST2/Tetherin Restriction on HIV-1 Release through a Non-canonical Autophagy Pathway

Abstract

BST2 (bone marrow stromal antigen 2)/tetherin is a restriction factor of enveloped viruses, which blocks the release of viral particles. HIV-1 encodes proteins that antagonize this innate barrier, including the accessory protein Vpu. Here, we investigate whether the autophagy pathway and/or ATG proteins are hijacked by HIV-1 Vpu to circumvent BST2 restriction of viral release. We report that BST2 and Vpu are present in LC3-positive compartments. We found that Vpu selectively interacts with the ATG8 ortholog LC3C through the Vpu L₆₃VEM₆₆ sequence. This sequence is required for Vpu to antagonize BST2 restriction. LC3C expression favors the removal of BST2 from the HIV-1 budding site, and thus HIV-1 release in BST2-expressing cells. Additionally, ATG5 and beclin 1/ATG6, but not all the components of the autophagy pathway, act with LC3C to facilitate Vpu antagonism of BST2 restriction. Altogether, our data support the view that a non-canonical autophagy pathway reminiscent of LC3-associated phagocytosis contributes to Vpu counteraction of BST2 restriction.

Keywords: ATG; ATG5; BST2; HIV-1; LC3-associated phagocytosis; LC3C; Vpu; autophagy; restriction; tetherin.