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bioRxiv · 10.1101/2021.06.10.447995

MKP-1 modulates Ubiquitination/Phosphorylation of TLR signaling

Talreja, J.·Bauerfeld, C.·Wang, X.·Hafner, M.·Liu, Y.·Samavati, L.
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Abstract

Ubiquitination and phosphorylation are reversible post-translational protein modifications regulating physiological and pathological processes. MAPK phosphatase (MKP)-1 regulates innate and adaptive immunity. The multifaceted roles of MKP-1 were attributed to dephosphorylation of p38 and JNK mitogen activated kinases (MAPKs). We show that the lack of MKP-1 modulates the landscape of ubiquitin ligases and deubiquitinase enzymes (DUBs). MKP-1 deficient mice showed an aberrant regulation of several DUBs and increased expression of proteins and genes involved in IL-1/TLR signaling upstream of MAPK, including IL-1R1, IRAK1, TRAF6, phosphorylated TAK1 and an increased K63-polyubiquitination on TRAF6. Increased K63-polyubiquitination on TRAF6 was associated with an enhanced phosphorylated form of A20. Among abundant DUBs, Ubiquitin-specific-protease-13 (USP13), which cleaves polyubiquitin- chains on client proteins, was substantially enhanced in murine MKP-1 deficient BMDMs. An inhibitor of USP13 decreased the K63-polyubiquitination on TRAF6, TAK1-phosphorylation, IL-1{beta} and TNF- induction in response to LPS in BMDMs. Our data show for the first time that MKP-1 modulates the ligase activity of TRAF6 through modulation of specific DUBs.

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Talreja, J., Bauerfeld, C., Wang, X., Hafner, M., Liu, Y., Samavati, L.. 2021-06-11. MKP-1 modulates Ubiquitination/Phosphorylation of TLR signaling. https://doi.org/10.1101/2021.06.10.447995

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