SFTSV nucleoprotein mediates DNA sensor cGAS degradation to evade cGAS-dependent antiviral responses.

Abstract

Abstract Cyclic GMP-AMP synthase (cGAS) is an important DNA pattern recognition receptor that mediates the antiviral innate immune responses by sensing intracellular self and non-self DNA. A tick-borne emerging bunyavirus, Severe fever with thrombocytopenia syndrome virus (SFTSV) is an RNA virus that causes a severe viral hemorrhagic fever in East and Southeast Asia countries with a high case fatality rate of up to 30%. However, it remains elusive whether cGAS is capable of recognizing SFTSV infection. Here, we uncovered a novel mechanism of the interplay between DNA sensor cGAS and RNA virus SFTSV. SFTSV infection triggered the relocalization of mitochondrial DNA, which led to the upregulation of cGAS transcription and expression in striking levels. Thus, the invasion of SFTSV was recognized by cGAS to initiate the activation of cGAS-dependent type Ⅰ interferon antiviral immune responses, indicating that cGAS is important for innate immunity against SFTSV infection. In addition, our results showed that SFTSV nucleoprotein (NP) could function as novel viral virulence factor, which mediated the degradation of cGAS and therefore suppressed the production of type Ⅰ interferon. Mechanically, NP promoted cGAS degradation in an autophagy-dependent manner by linking the 161-382 domain of cGAS to LC3. Taken together, our results unravel a novel army race between SFTSV and host cell innate immunity, illustrating a novel antagonistic mechanism employed by SFTSV NP to inhibit cGAS-dependent antiviral innate immune responses to activate the type I interferon pathway.