School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, Guangdong 510006, China.
Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Cells. 2019 Mar 15;8(3):248. doi: 10.3390/cells8030248.
Autophagy is a highly- evolutionarily-conserved catabolic pathway activated by various cellular stresses. Recently, non-canonical autophagy (NCA), which does not require all of the ATG proteins to form autophagosome or autophagosome-like structures, has been found in various conditions. Moreover, mounting evidence has indicated that non-canonical LC3 lipidation (NCLL) may reflect NCA. We and others have reported that niclosamide (Nic), an anti-helminthic drug approved by the Food and Drug Administration, could induce canonical autophagy via a feedback downregulation of mTOR complex 1. In this study, we found that Nic could also induce NCLL, which is independent of the ULK1 complex and Beclin 1 complex, but dependent on ubiquitin-like conjugation systems. Although bafilomycin A1 and concanamycin A, two known V-ATPase inhibitors, significantly inhibited Nic-induced NCLL, Nic-induced NCLL was demonstrated to be independent of V-ATPase. In addition, the Golgi complex and vimentin were involved in Nic-induced NCLL, which might be a platform or membrane source for Nic-induced LC3-positive structures. These results would be helpful to broaden our understanding of the working mechanisms of Nic and evaluate its pharmacological activities in diseases.
自噬是一种高度进化保守的降解途径，可被多种细胞应激激活。最近，在各种条件下发现了非典型自噬（NCA），其不需要所有 ATG 蛋白形成自噬体或自噬体样结构。此外，越来越多的证据表明，非典型 LC3 脂质化（NCLL）可能反映了 NCA。我们和其他人已经报道过，氯硝柳胺（Nic），一种被美国食品和药物管理局批准的抗蠕虫药物，通过反馈下调 mTOR 复合物 1 可以诱导经典自噬。在这项研究中，我们发现 Nic 还可以诱导 NCLL，这与 ULK1 复合物和 Beclin 1 复合物无关，但依赖于泛素样连接系统。虽然两种已知的 V-ATPase 抑制剂巴弗洛霉素 A1 和康纳霉素 A 显著抑制了 Nic 诱导的 NCLL，但 Nic 诱导的 NCLL 被证明与 V-ATPase 无关。此外，高尔基体复合物和波形蛋白参与了 Nic 诱导的 NCLL，这可能是 Nic 诱导的 LC3 阳性结构的平台或膜源。这些结果有助于拓宽我们对 Nic 作用机制的理解，并评估其在疾病中的药理学活性。
