TY - JOUR T1 - MKP-1 modulates ubiquitination/phosphorylation of TLR signaling JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202101137 VL - 4 IS - 12 SP - e202101137 AU - Jaya Talreja AU - Christian Bauerfeld AU - Xiantao Wang AU - Markus Hafner AU - Yusen Liu AU - Lobelia Samavati Y1 - 2021/12/01 UR - https://www.life-science-alliance.org/content/4/12/e202101137.abstract N2 - Ubiquitination and phosphorylation are reversible posttranslational 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 MAPKs. We show that the lack of MKP-1 modulates the landscape of ubiquitin ligases and deubiquitinase enzymes (DUBs). MKP-1−/− 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-1β, and TNF-α 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. ER -