The Endoplasmic Reticulum ATP13A1 is Essential for MAVS‐Mediated Antiviral Innate Immunity

RIG‐I‐MAVS signaling pathway is essential for efficient innate immune response against virus infection. Though many components have been identified in RIG‐I pathway and it can be partially reconstituted in vitro, detailed mechanisms involved in cells are still unclear. Here, a genome‐wide CRISPR‐Cas9 screen is performed using an engineered cell line IFNB‐P2A‐GSDMD‐N, and ATP13A1, a putative dislocase located on the endoplasmic reticulum, is identified as an important regulator of RIG‐I pathway. ATP13A1 deficiency abolishes RIG‐I‐mediated antiviral innate immune response due to compromised MAVS stability and crippled signaling potency of residual MAVS. Moreover, it is discovered that MAVS is subject to protease‐mediated degradation in the absence of ATP13A1. As homozygous Atp13a1 knockout mice result in developmental retardation and embryonic lethality, Atp13a1 conditional knockout mice are generated. Myeloid‐specific Atp13a1‐deficient mice are viable and susceptible to RNA virus infection. Collectively, the findings reveal that ATP13A1 is indispensable for the stability and activation of MAVS and a proper antiviral innate immune response.