An Endoplasmic Reticulum Microprotein Suppresses Antiviral Innate Immune Response By Targeting MAVS

A large number of genes originally defined as non-coding RNA can also encode microproteins/proteins.The biological functions of these hidden microproteins/proteins are still unclear.Here,we discover a highly conserved 59-aa microprotein(998 ORF)encoded by the long non-coding transcript LINC00998,which is located on the endoplasmic reticulum membrane.Functional studies show that deficiency of LINC00998 significantly enhances the production of type Ⅰ IFN(IFNβ)in cells upon polvriboinsine-polyribocyaidylic acid(PolyI:C)transfection.Further,supplementing cells expressing shLINC00998 with 998 ORF remarkably rescues the effects caused by deficiency of LINC00998,suggesting that 998 ORF negatively regulates the RIG-I-like receptor(RLR)-mediated antiviral innate immune response.And then we find that this regulation is related to its interaction with mitochondrial antiviral signaling protein(MAVS).Further,998 ORF knockout mice are generated by CRISPR/Cas9,and 998 ORF knockout mice has no obviously developmental defects,but compared to wild type mice,MEF cells derived from 998 ORF knockout mice are found that shows much stronger antiviral immune signals upon PolyI:C challenge.Therefore,we have established an important role of a cross-organelle interaction model in regulating MAVS-mediated antiviral innate immune signal transduction.