International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
Acta Pharmacol Sin. 2023 Dec;44(12):2445-2454. doi: 10.1038/s41401-023-01139-x. Epub 2023 Aug 14.
Acute pancreatitis (AP) is an inflammatory disease of the exocrine pancreas. Disruptions in organelle homeostasis, including macroautophagy/autophagy dysfunction and endoplasmic reticulum (ER) stress, have been implicated in human and rodent pancreatitis. Syntaxin 17 (STX17) belongs to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) subfamily. The Qa-SNARE STX17 is an autophagosomal SNARE protein that interacts with SNAP29 (Qbc-SNARE) and the lysosomal SNARE VAMP8 (R-SNARE) to drive autophagosome-lysosome fusion. In this study, we investigated the role of STX17 in the pathogenesis of AP in male mice or rats induced by repeated intraperitoneal injections of cerulein. We showed that cerulein hyperstimulation induced AP in mouse and rat models, which was characterized by increased serum amylase and lipase activities, pancreatic edema, necrotic cell death and the infiltration of inflammatory cells, as well as markedly decreased pancreatic STX17 expression. A similar reduction in STX17 levels was observed in primary and AR42J pancreatic acinar cells treated with CCK (100 nM) in vitro. By analyzing autophagic flux, we found that the decrease in STX17 blocked autophagosome-lysosome fusion and autophagic degradation, as well as the activation of ER stress. Pancreas-specific STX17 knockdown using adenovirus-shSTX17 further exacerbated pancreatic edema, inflammatory cell infiltration and necrotic cell death after cerulein injection. These data demonstrate a critical role of STX17 in maintaining pancreatic homeostasis and provide new evidence that autophagy serves as a protective mechanism against AP.
急性胰腺炎（AP）是一种胰腺外分泌腺的炎症性疾病。细胞器稳态的破坏，包括巨自噬/自噬功能障碍和内质网（ER）应激，与人类和啮齿动物胰腺炎有关。突触结合蛋白 17（STX17）属于可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体（SNARE）亚家族。Qa-SNARE STX17 是一种自噬体 SNARE 蛋白，可与 SNAP29（Qbc-SNARE）和溶酶体 SNARE VAMP8（R-SNARE）相互作用，以驱动自噬体-溶酶体融合。在这项研究中，我们研究了 STX17 在反复腹腔注射 cerulein 诱导的雄性小鼠或大鼠 AP 发病机制中的作用。我们表明，cerulein 过度刺激诱导了小鼠和大鼠模型中的 AP，其特征是血清淀粉酶和脂肪酶活性增加、胰腺水肿、坏死性细胞死亡和炎症细胞浸润，以及胰腺 STX17 表达明显降低。在体外，用 CCK（100 nM）处理原代和 AR42J 胰腺腺泡细胞时，也观察到 STX17 水平的相似降低。通过分析自噬流，我们发现 STX17 的减少阻断了自噬体-溶酶体融合和自噬降解，以及 ER 应激的激活。使用腺病毒-shSTX17 特异性敲低胰腺 STX17 进一步加剧了 cerulein 注射后胰腺水肿、炎症细胞浸润和坏死性细胞死亡。这些数据表明 STX17 在维持胰腺稳态方面起着关键作用，并提供了新的证据表明自噬是一种针对 AP 的保护机制。
