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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.

Author information

1
Center for Precision Medicine, Department of Medicine, University of Missouri, Columbia, Missouri, USA.
2
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.
3
State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
4
Departments of Surgery and Molecular Microbiology and Immunology, University of Missouri, Columbia, Missouri, USA.
5
Department of Microbiology and Immunology, University of Rochester, School of Medicine and Dentistry, Rochester, New York, USA.

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-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.

KEYWORDS:

Immunology; Inflammation; Innate immunity

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