sNASP inhibits TLR signaling to regulate immune response in sepsis

• Published in: The Journal of clinical investigation 2018-06, Vol.128 (6), p.2459-2472
• Main Authors: Yang, Feng-Ming, Zuo, Yong, Zhou, Wei, Xia, Chuan, Hahm, Bumsuk, Sullivan, Mark, Cheng, Jinke, Chang, Hui-Ming, Yeh, Edward Th
• Format: Article
• Language: English
• Subjects: Cellular signal transduction; Genetic aspects; Immune response; Sepsis; Toll-like receptors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI95720

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-1β, TNF-α, and IFN-γ 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.