Human lymphocyte antigen B‐associated transcript 2, 3, and 5 polymorphisms and haplotypes are associated with susceptibility of Kawasaki disease and coronary artery aneurysm

Hsieh, Yao Yuan; Lin, Ying; Chang, Chi Chen; Chen, Da Yuan; Hsu, Chiung‐Wen; Lo, Ming Min; Hsu, Kung Hao; Tsai, Fuu Jen

doi:10.1002/jcla.20409

Cited by 27 publications

(21 citation statements)

References 28 publications

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“…Several gene studies for coronary aneurysm formation in KD have suggested the involvement of genetic factors including IL-10, ITPKC, HLA-E, HLA-B associated transcript 2, 3, and 5, and ITPR3. [11][12][13][14][15][16] These genes are associated with immune-regulatory response and are involved in cardiovascular-related pathogenesis, which would contribute to susceptibility to coronary abnormalities in KD.…”

Section: Discussionmentioning

confidence: 99%

High neutrophil : lymphocyte ratio is associated with refractory Kawasaki disease

Cho

Bak

Kim

et al. 2017

Pediatrics International

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Section: Discussionmentioning

confidence: 99%

High neutrophil : lymphocyte ratio is associated with refractory Kawasaki disease

Cho

Bak

Kim

et al. 2017

Pediatrics International

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“…BAT5 belongs to a cluster of genes within the human major histocompatibility complex (MHC) class III, indicating that BAT5 may regulate immunity [6] – [7] . In humans, BAT5 polymorphism has been associated with susceptibility to Kawasaki disease and coronary artery aneurysm [8] . In pigs, a single nucleotide polymorphism in BAT5 was found to associate with back fat thickness [9] , suggesting that BAT5 might be involved in adipose tissue function and lipid metabolism.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and Pharmacological Characterization of the Human Lymphocyte Antigen B-Associated Transcript 5 (BAT5/ABHD16A)

et al. 2014

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BackgroundHuman lymphocyte antigen B-associated transcript 5 (BAT5, also known as ABHD16A) is a poorly characterized 63 kDa protein belonging to the α/β-hydrolase domain (ABHD) containing family of metabolic serine hydrolases. Its natural substrates and biochemical properties are unknown.Methodology/Principal FindingsAmino acid sequence comparison between seven mammalian BAT5 orthologs revealed that the overall primary structure was highly (≥95%) conserved. Activity-based protein profiling (ABPP) confirmed successful generation of catalytically active human (h) and mouse (m) BAT5 in HEK293 cells, enabling further biochemical characterization. A sensitive fluorescent glycerol assay reported hBAT5-mediated hydrolysis of medium-chain saturated (C14∶0), long-chain unsaturated (C18∶1, C18∶2, C20∶4) monoacylglycerols (MAGs) and 15-deoxy-Δ12,14-prostaglandin J2-2-glycerol ester (15d-PGJ2-G). In contrast, hBAT5 possessed only marginal diacylglycerol (DAG), triacylglycerol (TAG), or lysophospholipase activity. The best MAG substrates were 1-linoleylglycerol (1-LG) and 15d-PGJ2-G, both exhibiting low-micromolar Km values. BAT5 had a neutral pH optimum and showed preference for the 1(3)- vs. 2-isomers of MAGs C18∶1, C18∶2 and C20∶4. Inhibitor profiling revealed that β-lactone-based lipase inhibitors were nanomolar inhibitors of hBAT5 activity (palmostatin B > tetrahydrolipstatin > ebelactone A). Moreover, the hormone-sensitive lipase inhibitor C7600 (5-methoxy-3-(4-phenoxyphenyl)-3H-[1], [3], [4]oxadiazol-2-one) was identified as a highly potent inhibitor (IC50 8.3 nM). Phenyl and benzyl substituted analogs of C7600 with increased BAT5 selectivity were synthesized and a preliminary SAR analysis was conducted to obtain initial insights into the active site dimensions.Conclusions/SignificanceThis study provides an initial characterization of BAT5 activity, unveiling the biochemical and pharmacological properties with in vitro substrate preferences and inhibitor profiles. Utilization of glycerolipid substrates and sensitivity to lipase inhibitors suggest that BAT5 is a genuine lipase with preference for long-chain unsaturated MAGs and could in this capacity regulate glycerolipid metabolism in vivo as well. This preliminary SAR data should pave the way towards increasingly potent and BAT5-selective inhibitors.

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“…A variety of diseases, ranging from cancer to autoimmune disorders and diabetes, are linked to Bag6 (33)(34)(35)(36)(37). Despite this demonstrated importance, structural characterization of the Bag6 complex is lacking.…”

mentioning

confidence: 99%

Bag6 complex contains a minimal tail-anchor–targeting module and a mock BAG domain

Mock

Chartron

Zaslaver

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

129

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BCL2-associated athanogene cochaperone 6 (Bag6) plays a central role in cellular homeostasis in a diverse array of processes and is part of the heterotrimeric Bag6 complex, which also includes ubiquitin-like 4A (Ubl4A) and transmembrane domain recognition complex 35 (TRC35). This complex recently has been shown to be important in the TRC pathway, the mislocalized protein degradation pathway, and the endoplasmic reticulum-associated degradation pathway. Here we define the architecture of the Bag6 complex, demonstrating that both TRC35 and Ubl4A have distinct C-terminal binding sites on Bag6 defining a minimal Bag6 complex. A crystal structure of the Bag6–Ubl4A dimer demonstrates that Bag6–BAG is not a canonical BAG domain, and this finding is substantiated biochemically. Remarkably, the minimal Bag6 complex defined here facilitates tail-anchored substrate transfer from small glutamine-rich tetratricopeptide repeat-containing protein α to TRC40. These findings provide structural insight into the complex network of proteins coordinated by Bag6.

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Human lymphocyte antigen B‐associated transcript 2, 3, and 5 polymorphisms and haplotypes are associated with susceptibility of Kawasaki disease and coronary artery aneurysm

Abstract: BAT2 -8671, BAT3 8854, and BAT5 22655, 9569 polymorphisms as well as BAT haplotypes (ATTGTG and ATCATG) might be associated with higher KD susceptibility and CAA formation. HLA-B region polymorphisms might contribute to the pathogenesis of KD and CAA.

Cited by 27 publications

References 28 publications

High neutrophil : lymphocyte ratio is associated with refractory Kawasaki disease

High neutrophil : lymphocyte ratio is associated with refractory Kawasaki disease

Biochemical and Pharmacological Characterization of the Human Lymphocyte Antigen B-Associated Transcript 5 (BAT5/ABHD16A)

Bag6 complex contains a minimal tail-anchor–targeting module and a mock BAG domain

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