MKP-1 modulates ubiquitination/phosphorylation of TLR signaling.

Autor:	Talreja J; Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI, USA., Bauerfeld C; Department of Pediatrics, Division of Critical Care, Central Michigan University, Mount Pleasant, MI, USA., Wang X; Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD, USA., Hafner M; Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD, USA., Liu Y; Center for Perinatal Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, USA., Samavati L; Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Wayne State University School of Medicine and Detroit Medical Center, Detroit, MI, USA ay6003@wayne.edu.; Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
Jazyk:	angličtina
Zdroj:	Life science alliance [Life Sci Alliance] 2021 Sep 27; Vol. 4 (12). Date of Electronic Publication: 2021 Sep 27 (Print Publication: 2021).
DOI:	10.26508/lsa.202101137
Abstrakt:	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. (© 2021 Talreja et al.)
Databáze:	MEDLINE
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