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

Abstract

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.

Autophagy‐related protein 5 (ATG5) interacts with bone marrow stromal cell antigen 2 (BST2) to stimulate HBV replication through antagonizing the antiviral activity of BST2

“…We, therefore, propose that the interaction of ATG5, BST2, and HBx may also affect BST2 degradation to promote HBV replication. In addition, we found HBx did not affect ATG5‐BST2 interaction, which was different from the case that ATG5 preferentially target virus‐tethered BST2 in HIV infection 24 . However, the specific mechanisms need to be further studied.…”

“…In addition, we found HBx did not affect ATG5-BST2 interaction, which was different from the case that ATG5 preferentially target virus-tethered BST2 in HIV infection. 24 However, the specific mechanisms need to be further studied.…”

“…It comprises a glycophosphatidylinositol (GPI) anchor at the C terminus, a coiled coil structure in extracellular domain, a small cytosolic domain, and a transmembrane (TM) helix at the N terminus. 24,39 Caballero et al demonstrated that BST2 inhibited HIV release by infiltrating virion envelopes with their membrane anchor. 40 It had also been reported that BST2 was a limiting factor for HBV.…”

“…BST2 has been reported to inhibit the release of enveloped viruses such as HBV and HIV. 23,24 We, therefore, investigated the regulation of ATG5 and BST2 on HBV replication in HepAD38 with inducible HBV replication and HBV-infected NTCP-HepG2 cells. 26,27 We confirmed again that ATG5 knockdown significantly increased BST2 at mRNA and protein levels in both HepAD38 (Figure 3A infected NTCP-HepG2.…”

“…23 A recent study demonstrated that ATG5 selectively targeted and degraded virus-tethered BST2 in HIV infection. 24 We, therefore, hypothesized that the knockdown of ATG5 inhibits HBV replication through interacting with BST2 and activating the JAK-STAT pathway.…”