sNASP inhibits TLR signaling to regulate immune response in sepsis
Feng-Ming Yang, … , Hui-Ming Chang, Edward T.H. Yeh
Feng-Ming Yang, … , Hui-Ming Chang, Edward T.H. Yeh
Published May 7, 2018
Citation Information: J Clin Invest. 2018;128(6):2459-2472. https://doi.org/10.1172/JCI95720.
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sNASP inhibits TLR signaling to regulate immune response in sepsis

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.

Authors

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

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Figure 8

sNasp S158A-KI mice are more susceptible to sepsis due to defective immune response.

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sNasp S158A-KI mice are more susceptible to sepsis due to defective immu...
(A) Survival curves of WT and NASP S158A-KI (NASPm) mice following CLP (n = 10 per group per experiment). Bacterial load (as CFU) in the lung, liver, and peritoneal fluid (B), serum cytokines (C), and circulating leukocytes (CD11b+) (D) in WT and NASPm mice were measured 24 hours after sham treatment or CLP (n = 10 per group per experiment). (E) Model of TLR4 signaling regulated by sNASP. (1) Stimulation of TLR4 by LPS results in recruitment of IRAK4, CK2, and the TRAF6/sNASP complex. (2) CK2 phosphorylates sNASP. (3) p-sNASP is released from TRAF6. (4) TRAF6 autoubiquitination is followed by TAK-1 and IKK kinase activation and cytokine production. (F) IP with anti-NASP followed by IB with phosphorylated serine (pSerine), TRAF6, or NASP in human bone marrow mononuclear cells following LPS treatment. TCL IB was done with antibody against TRAF6 or β-actin. Results represent a minimum of 2 independent experiments with 10 mice each (A–D) or at least 3 (F) independent experiments. Data in B–D are mean ± SE for each group. *P < 0.05, **P < 0.01 (1-way ANOVA).