TY - JOUR
T1 - sNASP inhibits TLR signaling to regulate immune response in sepsis
AU - Yang, Feng Ming
AU - Zuo, Yong
AU - Zhou, Wei
AU - Xia, Chuan
AU - Hahm, Bumsuk
AU - Sullivan, Mark
AU - Cheng, Jinke
AU - Chang, Hui Ming
AU - Yeh, Edward T.H.
N1 - Funding Information:
Supported by Strategic Hire of the University of Missouri (grant to ETHY); National Natural Science Foundation of China (grant 91229202), the National Basic Research Program of China (973 Program; grant 2013CB910902), the Specialized Research Fund for the Doctoral Program of Higher Education (grant 20120073110073), and Shanghai Committee of Science and Technology (grant 11DZ2260200) (to JC); and NIH R21 AI127404 (to BH). ETHY is the Frances T. McAndrew Chair of the University of Missouri. We would like to thank Runsheng Wang (MD Anderson Cancer Center) for technical assistance.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI95720
DO - 10.1172/JCI95720
M3 - Article
C2 - 29733298
AN - SCOPUS:85048279146
VL - 128
SP - 2459
EP - 2472
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 6
ER -