探討TAPE-like (TAPE-L) 分子在先天免疫調控及細菌感染之角色

Abstract

Innate immune recognition of pathogen infection is mainly mediated by pattern recognition receptors (PRRs) upon sensing the pathogen molecular signatures, termed pathogen-associated molecular patterns (PAMPs). Toll-like receptors (TLRs) represent a prototype family of PRRs to detect a variety of microbial components and trigger innate immune defenses. Much attention and progress have focused on understanding the downstream signaling pathways linking TLRs to innate immune activation. Previous work from our lab uncovered an innate immune regulator, called TAPE (TBK1-associated protein in endolysosome), which is involved in TLR3, TLR4, and RIG-I-like receptor signaling pathways. Furthermore, a TAPE paralog protein termed TAPE-like (TAPE-L) was identified by blast analysis. Our preliminary biochemical analyses showed that TAPE-L was a potent NF-қB activator and capable of regulating the surface TLR pathways. We further used gene knockout mice, primary macrophages and THP-1 cells to assess whether TAPE-L functions as an innate immune regulator. Results showed that gene silencing of TAPE-L impaired the activation of NF-κB and inflammatory cytokine production upon TLR agonist stimulation, indicating that TAPE-L was involved in linking surface TLRs signaling to the activation of NF-κB. Tape-l -/- cells also displayed defective LPS-induced IκB degradation and cytokine responses. The resistance to LPS-induced sepsis in Tape-l -/- mice supports the in vivo role of TAPE-L in TLR4 signaling. Furthermore, Tape-l -/- mice were more susceptible to gram-negative bacterial infection than wild type mice, suggesting the in vivo significance of TAPE-L for antibacterial defenses. TAPE-L-deficient macrophages also showed impaired inflammatory cytokine responses to bacteria, indicating that TAPE-L facilitated the inflammation response against bacterial infection. Collectively, my thesis work demonstrated that TAPE-L is essential for activating the surface TLRs pathway and required for antibacterial immunity. My future directions will aim to explore the potential roles of TAPE-L in regulating other TLR or PRR pathways during bacterial infections.