Abstract
MAVS is essential for antiviral immunity, but the molecular mechanisms responsible for its tight regulation remain poorly understood. Here, we show that NLK inhibits the antiviral immune response during viral infection by targeting MAVS for degradation. NLK depletion promotes virus-induced antiviral cytokine production and decreases viral replication, which is potently rescued by the reintroduction of NLK. Moreover, the depletion of NLK promotes antiviral effects and increases the survival times of mice after infection with VSV. NLK interacts with and phosphorylates MAVS at multiple sites on mitochondria or peroxisomes, thereby inducing the degradation of MAVS and subsequent inactivation of IRF3. Most importantly, a peptide derived from MAVS promotes viral-induced IFN-β production and antagonizes viral replication in vitro and in vivo. These findings provide direct insights into the molecular mechanisms by which phosphorylation of MAVS regulates its degradation and influences its activation and identify an important peptide target for propagating antiviral responses.
Highlights
mitochondrial antiviral-signaling protein (MAVS) is essential for antiviral immunity, but the molecular mechanisms responsible for its tight regulation remain poorly understood
Because IFN-β activation requires coordination between the activation of nuclear factor (NF)-κB and IRF3, we used an interferonstimulated response element (ISRE) luciferase reporter that required only IRF3 activation to evaluate whether the NLKdependent inhibition of type I interferon was dependent on its inhibitory effect on ISRE signaling
Sendai virus (SeV)-induced ISRE luciferase reporter activity was potently inhibited by Nemo-like kinase (NLK), suggesting that NLK inhibited IFN-β activation by blocking IRF3 signaling (Fig. 1c)
Summary
MAVS is essential for antiviral immunity, but the molecular mechanisms responsible for its tight regulation remain poorly understood. A peptide derived from MAVS promotes viral-induced IFN-β production and antagonizes viral replication in vitro and in vivo These findings provide direct insights into the molecular mechanisms by which phosphorylation of MAVS regulates its degradation and influences its activation and identify an important peptide target for propagating antiviral responses. The RNA helicases RIG-I and MDA5 function as cytoplasmic RNA sensors that can recognize both the Sendai virus (SeV) and vesicular stomatitis virus (VSV) RNA viruses, resulting in recruitment of the mitochondrial antiviral-signaling protein (MAVS; VISA, IPS-1, or Cardif) and TRAF3-dependent assembly of K63-linked polyubiquitin chains, which further activates the downstream signaling molecules TBK1 and IRF3, to achieve the type I interferon response after ligand recognition[8,9]. Despite the importance of RIG-I-like receptor (RLR)-mediated type I interferon signaling to the immune response, the molecular mechanisms responsible for the regulation of RLR-mediated signaling via the posttranscriptional modification of MAVS remain poorly understood
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