期刊
CELL REPORTS
卷 28, 期 3, 页码 804-+出版社
CELL PRESS
DOI: 10.1016/j.celrep.2019.06.048
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资金
- National Natural Science Foundation of China [31320103907, 31730094]
- National Key Research and Development Program Special Project [2016YFD0501607]
- Program for High-end talents of Yangzhou University
- Six Talent Peaks Program'' of Jiangsu Province [NY-028]
- Yangzhou University Science and Technology Innovation Team
- Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD)
- Postgraduate Research & Practice Innovation Program of Jiangsu Province [KYCX18_2377]
- Fund for Excellent Doctoral Dissertations from Yangzhou University
- Yangzhou University International Academic Exchange Fund
Toll-like receptors (TLRs) activate innate immunity via interactions between their Toll/interleukin-1 (IL-1) receptor (TIR) domain and downstream adaptor proteins. Here we report that Salmonella Enteritidis produces a secreted protein (TcpS) that contains both a TIR domain and a coiled-coil domain. TcpS blocks MyD88- and TRIF-mediated TLR signaling, inhibits inflammatory responses, and promotes bacterial survival. Early-stage immune evasion by TcpS results in severe tissue damage in the late stage of infection and contributes to Salmonella virulence. TcpS-derived peptides inhibit nuclear factor kappa B (NF-kappa B) and mitogen-activated protein kinase (MAPK) activation and reduce lipopolysaccharide (LPS)-elicited systemic inflammation. Therapeutic peptide administration alleviates weight loss of mice infected with H1N1 influenza. Importantly, maximal TcpS-mediated TLR inhibition requires the critical TIR-TcpS residues Y191 and I284, as well as TcpS homodimerization via its N-terminal coiled-coil domain. Our study unveils a mechanism in which TcpS suppresses innate immunity via both its homodimerization and interaction with MyD88. TcpS is also a potential therapeutic agent for inflammation-associated diseases.
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