Dataset Information

ALPK1 phosphorylates myosin IIA modulating TNF-? 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)-?. Furthermore, all gouty patients expressed higher basal protein levels of ALPK1, myosin IIA, and plasma TNF-?, however those medicated with colchicine has shown reduced myosin IIA and TNF-? but not ALPK1. The findings suggest ALPK1 is a kinase that participates in the regulation of Golgi-derived TNF-? 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.

SUBMITTER: Lee CP

PROVIDER: S-EPMC4864424 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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ALPK1 phosphorylates myosin IIA modulating TNF-α trafficking in gout flares.

Lee Chi-Pin CP Chiang Shang-Lun SL Ko Albert Min-Shan AM Liu Yu-Fan YF Ma Che C Lu Chi-Yu CY Huang Chung-Ming CM Chang Jan-Gowth JG Kuo Tzer-Min TM Chen Chia-Lin CL Tsai Eing-Mei EM Ko Ying-Chin YC

Scientific reports 20160512

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-i ...[more]

PMID: 27169898

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Project description:BackgroundThere is a paucity of community-based data regarding the prevalence and impact of gout flares as these may often be self-managed. The aim of this study was to determine the prevalence of self-reported gout and gout flares, the use of urate-lowering therapy (ULT), and the association of gout flares with health-related quality of life (HRQoL) in a large community sample. Covariate associations with flare frequency and allopurinol use were also examined.MethodsThe South Australian Health Omnibus Survey is an annual, face-to-face population-based survey. Data collected in the 2017 survey included self-reported medically diagnosed gout, allopurinol use (first-line ULT in Australia), and gout attacks (flares) in the last 12 months, in addition to sociodemographic variables and health-related quality of life (HRQoL, SF-12). Data were weighted to the Australian Bureau of Statistics 2016 census data to reflect the South Australian population. Participants 25 years and over (n = 2778) were included in the analysis.ResultsThe prevalence of gout was 6.5% (95%CI 5.5, 7.5). Amongst participants with gout, 37.1% (95%CI 29.6, 45.3) reported currently using allopurinol, while 23.2% (95%CI 16.9, 21.0) reported prior use (38% discontinuation rate). Frequent flares (≥ 2 in the last year) were reported by 25% of participants with gout and were more likely with younger age, higher body mass index, and current allopurinol use (p < 0.05). The frequency of gout flares was associated with a lower physical HRQoL (p = 0.012). Current allopurinol use was reported by 51% of participants with frequent gout flares.ConclusionFlares were frequently reported by people with gout in the community. Gout flares were associated with reduced physical HRQoL. Almost one half of people with frequent gout flares were not receiving allopurinol, and current allopurinol use was associated with frequent gout flares, suggesting undertreated disease and suboptimal use of ULT. Determining covariate associations with flares and ineffective allopurinol use may identify means of improving treatment and reducing flares.

Dataset Information

ALPK1 phosphorylates myosin IIA modulating TNF-? trafficking in gout flares.

Publications

ALPK1 phosphorylates myosin IIA modulating TNF-α trafficking in gout flares.

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