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J Clin Invest. 2018 Jun 1;128(6):2459-2472. doi: 10.1172/JCI95720. Epub 2018 May 7.

sNASP inhibits TLR signaling to regulate immune response in sepsis.

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Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, Missouri, USA.
Department of Biochemistry and Molecular Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri, USA.
Department of Microbiology and Immunology, University of Rochester, School of Medicine and Dentistry, Rochester, New York, USA.


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.


Immunology; Inflammation; Innate immunity

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