Hfe Inhibits Type I Ifns Signaling By Targeting The Sqstm1-Mediated Mavs Autophagic Degradation

Iron metabolism is involved in numerous physiological processes such as erythropoiesis, oxidative metabolism. However, thein vivophysiological functions of the iron metabolism-related geneHfein immune response during viral infection remain poorly understood. Here, we identified 5 iron metabolism-associated genes specifically affected during RNA virus infection by a high-throughput assay and further found that HFE was a key negative regulator of RIG-I-like receptors (RLR)-mediated type I interferons (IFNs) signaling. RNA virus infection inhibited the binding of HFE to MAVS (mitochondrial antiviral signaling protein) and blocked MAVS degradation via selective autophagy. HFE mediated MAVS autophagic degradation by binding to SQSTM1/p62. Depletion ofHfeabrogated the autophagic degradation of MAVS, leading to the stronger antiviral immune response. These findings established a novel regulatory role of selective autophagy in innate antiviral immune response by the iron metabolism-related geneHfe. These data further provided insights into the crosstalk among iron metabolism, autophagy, and innate immune response.