ATG4B antagonizes antiviral immunity by GABARAP-directed autophagic degradation of TBK1

TBK1 (TANK binding kinase 1) is an essential kinase of antiviral immunity, yet the regulatory mechanisms responsible for its stringent control via autophagy are not fully understood. Here, we identify the macroautophagy/autophagy-related cysteine protease ATG4B as a negative regulator of human antiviral immune responses by targeting TBK1 for autophagic degradation at the advanced stage of viral infection. Mechanistically, ATG4B serves as an adaptor for recruiting TBK1 to GABARAP (GABA type A receptor-associated protein), which subsequently leads to the TBK1-GABARAP interaction through the LC3-interacting region (LIR) motif of TBK1 ULD domain. Moreover, pharmacological ATG4B inhibitor, a small molecule named S130, contributes to host defense against viral infection and blocks ATG4B-dependent autophagic degradation of TBK1. Accordingly, S130 increases antiviral response and inhibits the VSV infection both in vitro and in vivo. Altogether, our study reveals the regulatory role of ATG4B in modulating TBK1-centered type I interferon (IFN) signaling, and indicates that ATG4B suppression can provide a potential therapy target for viral infection.