1. sNASP inhibits TLR signaling to regulate immune response in sepsis
- Author
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Yang, Feng-Ming, Zuo, Yong, Zhou, Wei, Xia, Chuan, Hahm, Bumsuk, Sullivan, Mark, Cheng, Jinke, Chang, Hui-Ming, and Yeh, Edward T.H.
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Toll-like receptors -- Research ,Sepsis -- Genetic aspects -- Research ,Immune response -- Research ,Cellular signal transduction -- Research ,Health care industry - Abstract
Many Toll-like receptors (TLRs) signal through TNF receptor-associated factor 6 (TRAF6) to activate innate immune responses. Here, we show that somatic nuclear autoantigenic sperm protein (sNASP) binds to TRAF6 to prevent TRAF6 autoubiquitination in unstimulated macrophages. Following LPS stimulation, a complex consisting of sNASP, TRAF6, IRAK4, and casein kinase 2 (CK2) is formed. CK2 phosphorylates sNASP at serine 158, allowing sNASP to dissociate from TRAF6. Free TRAF6 is then autoubiquitinated, followed by activation of downstream signaling pathways. In sNasp S158A knockin (S158A-KI) mice, LPS-treated macrophages could not phosphorylate sNASP, which remained bound to TRAF6. S158A-KI mice were more susceptible to sepsis due to a marked reduction in IL-1[beta], TNF-[alpha], and IFN-[gamma] production accompanied by an inability to clear bacteria and recruit leukocytes. Furthermore, phosphorylation-regulated release of sNASP from TRAF6 is observed following activation of TLR-1, -2, -4, -5, and -6. Thus, sNASP is a negative regulator of TLR signaling to modulate the innate immune response., Introduction The innate immune response is activated by pathogen-associated molecular patterns (PAMPs) through a family of Toll-like receptors (TLRs) (1, 2). TLR signaling can be classified into MyD88-dependent or MyD88-independent [...]
- Published
- 2018
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