Emerging roles of an innate immune regulator TAPE in Toll-like receptors, RIG-I-like receptors, and beyond

Abstract

Pattern-recognition receptors (PRRs) trigger innate immune defenses against pathogen infection via downstream signaling pathways linking to inflammation and cell-autonomous immunity like phagocytosis and autophagy. IKK family kinases, IKKα and IKKβ, function to relay PRR signals to proinflammatory cytokine production to amplify innate immune responses. TBK1, a non-canonical IKK kinase, links nucleic acid sensors to type I interferon induction against viral infection and also regulates the autophagic clearance of intracellular bacteria. TBK1-Associated Protein in Endolysosomes designated TAPE, also known as CC2D1A, is an innate immune regulator acting upstream of Trif to regulate the TLR3 and TLR4 pathways, or upstream of MAVS to regulate the cytosolic RIG-I-like receptor (RLR) pathways. To our best knowledge, TAPE is the first regulator implicated in both the endosomal TLR and cytosolic RLR pathways at such an early step. We are thus interested in investigating in vivo roles of TAPE in innate immunity and molecular mechanisms by which TAPE regulates TLRs, RLRs, and possibly other PRRs. TAPE conditional knockout (cKO) mice, in which TAPE is selectively disrupted in immune cells, have been generated for our study. Our results showed that upon influenza A virus infection, TAPE cKO mice exhibited a more severe mortality than wild type mice. Further, TAPE cKO mice were shown to be more susceptible to Salmonella Typhimurium infection but more resistant to LPS-induced septic shock. Notably, ex vivo results showed that TAPE was critical for the autophagic clearance of Salmonella Typhimurium. Together, our data support a critical role for TAPE in regulating innate immune defenses through TLRs, RLRs, and autophagy.