ATG5 selectively engages virus-tethered BST2/Tetherin in an LC3C-associated pathway

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 anti-viral state. The HIV-1 Vpu protein antagonizes BST2 antiviral functions, notably by subverting an LC3C-associated pathway, a key cell intrinsic anti-microbial mechanism. Here, we show that ATG5 associates with BST2 and acts as a signaling scaffold to trigger an LC3C-associated pathway induced by HIV-1 infection. This process is initiated at the plasma membrane through the recognition of virus-tethered BST2 by ATG5. 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 transducer of the LC3C-associated pathway induced by HIV-1 infection.