Biomedical Research Service, John D. Dingell VA Medical Center, and Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA.
Biochem Pharmacol. 2023 Dec;218:115889. doi: 10.1016/j.bcp.2023.115889. Epub 2023 Oct 29.
It is widely accepted that pancreatic islet β-cell failure and the onset of type 2 diabetes (T2DM) constitute an intricate interplay between the genetic expression of the disease and a host of intracellular events including increased metabolic (oxidative, endoplasmic reticulum) stress under the duress of glucolipotoxicity. Emerging evidence implicates unique roles for Caspase Recruitment Domain containing protein 9 (CARD9) in the onset of metabolic diseases, including obesity and insulin resistance. Mechanistically, CARD9 has been implicated in the regulation of p38MAPK and NFkB signaling pathways culminating in cellular dysfunction. Several regulatory factors, including B-cell lymphoma/leukemia 10 (BCL10) have been identified as modulators of CARD9 function in multiple cell types. Despite this evidence on regulatory roles of CARD9-BCL10 signalome in the onset of various pathological states, putative roles of this signaling module in islet β-cell dysfunction in metabolic stress remain less understood. This brief review is aimed at highlighting roles for CARD9 in islet β-cell function under acute (physiological insulin secretion) and long-term (cell dysfunction) exposure to glucose. Emerging roles of other signaling proteins, such as Rac1, BCL10 and MALT1 as contributors to CARD9 signaling in the islet β-cells are also reviewed. Potential avenues for future research toward the development of novel therapeutics for the prevention CARD9-BCL10-Rac1 (CBR) signalome-induced β-cell defects under metabolic stress are discussed.
人们普遍认为，胰岛β细胞衰竭和 2 型糖尿病（T2DM）的发生是疾病的基因表达与多种细胞内事件之间复杂相互作用的结果，包括在糖脂毒性胁迫下代谢（氧化、内质网）应激的增加。新出现的证据表明，胱天蛋白酶募集结构域蛋白 9（CARD9）在代谢疾病（包括肥胖和胰岛素抵抗）的发生中具有独特作用。从机制上讲，CARD9 被牵连到 p38MAPK 和 NFkB 信号通路的调节，最终导致细胞功能障碍。已经确定了几种调节因子，包括 B 细胞淋巴瘤/白血病 10（BCL10），作为 CARD9 在多种细胞类型中功能的调节剂。尽管有证据表明 CARD9-BCL10 信号组在各种病理状态的发生中具有调节作用，但该信号模块在代谢应激下胰岛β细胞功能障碍中的潜在作用仍知之甚少。这篇简短的综述旨在强调 CARD9 在胰岛β细胞功能中的作用，包括在急性（生理胰岛素分泌）和长期（细胞功能障碍）暴露于葡萄糖下的作用。还综述了其他信号蛋白（如 Rac1、BCL10 和 MALT1）在胰岛β细胞中作为 CARD9 信号的贡献者的新兴作用。讨论了针对代谢应激下 CARD9-BCL10-Rac1（CBR）信号组诱导的β细胞缺陷的新型治疗药物的未来研究的潜在途径。
