TBK1-associated Protein in Endolysosomes (TAPE) Is an Innate Immune Regulator Modulating the TLR3 and TLR4 Signaling Pathways

The innate immune system elicits the first wave of immune responses against pathogen infection. Its operational modes are complex and have yet to be defined. Here, we report the identification of an innate immune regulator termed TAPE (TBK1-associated protein in endolysosomes), previously known as CC2D1A/Freud-1/Aki-1, which modulates the TLR3 and TLR4 pathways. We found that TAPE activated the TBK1, NF-kappa B, and ERK pathways leading to IFN-beta and inflammatory cytokine induction. TAPE was shown to colocalize with endosomal marker Rab5 and lysosomal marker LAMP1 in mammalian cells, suggesting that TAPE resided in endolysosomes. Knockdown of TAPE selectively impaired the TLR3 and endocytic TLR4 pathways to IFN-beta induction. Furthermore, TAPE interacted and synergized with Trif to activate IFN-beta. TAPE knockdown failed to block Trif-mediated IFN-beta induction, whereas Trif knockdown impaired the TLR3 and TAPE cooperation on IFN-beta induction, suggesting that TAPE acts upstream of Trif. Together, our data demonstrate a central role for TAPE in linking TLR3 and TLR4 to innate immune defenses at an early step.