title: TBK1-associated protein in endolysosomes (TAPE) is an innate immune regulator modulating the TLR3 and TLR4 signaling pathways.
abstract: 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-κB, and ERK pathways leading to IFN-β 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-β induction. Furthermore, TAPE interacted and synergized with Trif to activate IFN-β. TAPE knockdown failed to block Trif-mediated IFN-β induction, whereas Trif knockdown impaired the TLR3 and TAPE cooperation on IFN-β 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.
authors.affiliation: Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Chang
authors.forename: Li-Chun
authors.initials: LC
authors.lastname: Lai
authors.forename: Hung-Chi
authors.initials: HC
authors.lastname: Cheng
authors.forename: Kuan-Ru
authors.initials: KR
authors.lastname: Chen
authors.forename: Ying-Zhang
authors.initials: YZ
authors.lastname: Syue
authors.forename: Hsueh-Chi
authors.initials: HC
authors.lastname: Lu
authors.forename: Wan-Ying
authors.initials: WY
authors.lastname: Lin
authors.forename: Shun-Hua
authors.initials: SH
authors.lastname: Chen
authors.forename: Huei-Sheng
authors.initials: HS
authors.lastname: Huang
authors.forename: Ai-Li
authors.initials: AL
authors.lastname: Shiau
authors.forename: Huan-Yao
authors.initials: HY
authors.lastname: Lei
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.forename: Pin
authors.initials: P
authors.lastname: Ling
mesh_terms: D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism*; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000378:metabolism*; D016899:Interferon-beta / Q000276:immunology / Q000378:metabolism; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
chemical_list: C512283:CC2D1A protein, human; D004268:DNA-Binding Proteins; D007155:Immunologic Factors; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases