title: ALPK1 phosphorylates myosin IIA modulating TNF-α trafficking in gout flares.
abstract: Gout is characterized by the monosodium urate monohydrate (MSU)-induced arthritis. Alpha kinase-1 (ALPK1) has shown to be associated with MSU-induced inflammation and gout. Here, we used bioinformatics, proteomics, cell models, and twenty in vitro human assays to clarify some of its role in the inflammatory response to MSU. We found myosin IIA to be a frequent interacting protein partner of ALPK1, binding to its N-terminal and forming a protein complex with calmodulin and F-actin, and that MSU-induced ALPK1 phosphorylated the myosin IIA. A knockdown of endogenous ALPK1 or myosin IIA significantly reduced the MSU-induced secretion of tumour necrosis factor (TNF)-α. Furthermore, all gouty patients expressed higher basal protein levels of ALPK1, myosin IIA, and plasma TNF-α, however those medicated with colchicine has shown reduced myosin IIA and TNF-α but not ALPK1. The findings suggest ALPK1 is a kinase that participates in the regulation of Golgi-derived TNF-α trafficking through myosin IIA phosphorylation in the inflammation of gout. This novel pathway could be blocked at the level of myosin by colchicine in gout treatment.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chi-Pin
authors.initials: CP
authors.lastname: Lee
authors.affiliation: Environment-Omics-Diseases Research Center, China Medical University Hospital, Taichung, Taiwan.|Department of Health Risk Management, College of Public Health, China Medical University, Taichung City, Taiwan.
authors.forename: Shang-Lun
authors.initials: SL
authors.lastname: Chiang
authors.affiliation: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig D-04103, Germany.
authors.forename: Albert Min-Shan
authors.initials: AM
authors.lastname: Ko
authors.affiliation: Department of Biomedical Sciences, College of Medicine Sciences and Technology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yu-Fan
authors.initials: YF
authors.lastname: Liu
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Che
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chi-Yu
authors.initials: CY
authors.lastname: Lu
authors.affiliation: Graduate Institute of Integrated Medicines, China Medical University, Taichung, Taiwan.
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Huang
authors.affiliation: Epigenome Research Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Jan-Gowth
authors.initials: JG
authors.lastname: Chang
authors.affiliation: Environment-Omics-Diseases Research Center, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Tzer-Min
authors.initials: TM
authors.lastname: Kuo
authors.affiliation: Department of Biomedical Sciences, College of Medicine Sciences and Technology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Eing-Mei
authors.initials: EM
authors.lastname: Tsai
authors.affiliation: Environment-Omics-Diseases Research Center, China Medical University Hospital, Taichung, Taiwan.|Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan.
authors.forename: Ying-Chin
authors.initials: YC
authors.lastname: Ko
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D003078:Colchicine / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D005822:Genetic Vectors / Q000378:metabolism; D006073:Gout / Q000097:blood / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D000072417:Protein Domains; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D017433:Protein Structure, Secondary; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism*; D014527:Uric Acid / Q000494:pharmacology
chemical_list: D016207:Cytokines; D014409:Tumor Necrosis Factor-alpha; D014527:Uric Acid; D011494:Protein Kinases; D024507:Nonmuscle Myosin Type IIA; D003078:Colchicine