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Edited by Jenny P.-Y. Ting, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, accepted by the editorial board on October 6, 2021 (received for review on April 20, 2021)

TNF receptor related factor 6 (TRAF6) is a key signaling molecule in the innate immune response. Here, we have identified a previously unrecognized role of protein phosphatase 4 in the regulation of TRAF6 activation through the dephosphorylation of natural TRAF6 inhibitors (somatic cell nuclear autoantigenic sperm proteins) to address the problem of Toll-like receptors. 4 Inflammatory response triggered.

Toll-like receptor (TLR) recognition of invading pathogens activates innate immunity through signaling pathways involving a variety of protein kinases and phosphatases. We have previously demonstrated that somatic cell nuclear autoantigen sperm protein (sNASP) binds to TNF receptor-related factor 6 (TRAF6) in the resting state. After TLR4 is activated, a signal complex composed of TRAF6, sNASP, interleukin (IL)-1 receptor-related kinase 4, and casein kinase 2 (CK2) is formed. Then CK2 phosphorylates sNASP, releases phosphorylated sNASP (p-sNASP) from TRAF6, and initiates downstream signaling pathways. Here, we found that protein phosphatase 4 (PP4) is a specific sNASP phosphatase, which negatively regulates TLR4-induced TRAF6 activation and its downstream signaling pathways. In terms of mechanism, PP4 is directly recruited by phosphorylated sNASP to dephosphorylate p-sNASP, thereby terminating the activation of TRAF6. After bacterial lipopolysaccharide (LPS) treatment, the ectopic expression of PP4 specifically inhibits the production of sNASP-dependent pro-inflammatory cytokines and downstream signal transduction, while silencing PP4 has the opposite effect. Primary macrophages and mice infected with recombinant adenovirus carrying the gene encoding PP4 (Ad-PP4) showed a significant reduction in IL-6 and TNF-α production. Due to the better ability to eliminate bacteria in the sepsis model, the survival rate of Ad-PP4-infected mice was significantly increased. These results indicate that serine/threonine phosphatase PP4 acts as a negative regulator of innate immunity by regulating the binding of sNASP and TRAF6.

Author contributions: research designed by F.-MY, H.-MC and ETHY; research conducted by F.-MY; analysis data of F.-MY, H.-MC and ETHY; F.-MY, H.-MC and ETHY wrote this paper.

The author declares no competing interests.

This article is directly contributed by PNAS. JPT is a guest editor invited by the editorial board.

This article contains online support information https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2107044118/-/DCSupplemental.

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