sNASP inhibits TLR signaling to regulate immune response in sepsis

Feng Ming Yang, Yong Zuo, Wei Zhou, Chuan Xia, Bumsuk Hahm, Mark Sullivan, Jinke Cheng, Hui Ming Chang, Edward T.H. Yeh

Research output: Contribution to journalArticle

5 Citations (Scopus)

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-1ß, TNF-a, and IFN-? 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.

Original languageEnglish
Pages (from-to)2459-2472
Number of pages14
JournalJournal of Clinical Investigation
Volume128
Issue number6
DOIs
Publication statusPublished - Jun 1 2018
Externally publishedYes

Fingerprint

TNF Receptor-Associated Factor 6
Toll-Like Receptors
Spermatozoa
Sepsis
Proteins
Casein Kinase II
Innate Immunity
Toll-Like Receptor 1
Macrophages
Toll-Like Receptor 2
Interleukin-1
Serine
Leukocytes
Phosphorylation
Bacteria

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yang, F. M., Zuo, Y., Zhou, W., Xia, C., Hahm, B., Sullivan, M., ... Yeh, E. T. H. (2018). sNASP inhibits TLR signaling to regulate immune response in sepsis. Journal of Clinical Investigation, 128(6), 2459-2472. https://doi.org/10.1172/JCI95720

sNASP inhibits TLR signaling to regulate immune response in sepsis. / Yang, Feng Ming; Zuo, Yong; Zhou, Wei; Xia, Chuan; Hahm, Bumsuk; Sullivan, Mark; Cheng, Jinke; Chang, Hui Ming; Yeh, Edward T.H.

In: Journal of Clinical Investigation, Vol. 128, No. 6, 01.06.2018, p. 2459-2472.

Research output: Contribution to journalArticle

Yang, FM, Zuo, Y, Zhou, W, Xia, C, Hahm, B, Sullivan, M, Cheng, J, Chang, HM & Yeh, ETH 2018, 'sNASP inhibits TLR signaling to regulate immune response in sepsis', Journal of Clinical Investigation, vol. 128, no. 6, pp. 2459-2472. https://doi.org/10.1172/JCI95720
Yang, Feng Ming ; Zuo, Yong ; Zhou, Wei ; Xia, Chuan ; Hahm, Bumsuk ; Sullivan, Mark ; Cheng, Jinke ; Chang, Hui Ming ; Yeh, Edward T.H. / sNASP inhibits TLR signaling to regulate immune response in sepsis. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 6. pp. 2459-2472.
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