Cui Lin, Zhang Qiong, Huang Yao, Yang Lei, Zhang Junhui, Jiang Xupin, Jia Jiezhi, Lv Yanling, Zhang Dongxia, Huang Yuesheng
Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
Department of Endocrinology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
Front Cardiovasc Med. 2021 Dec 23;8:796254. doi: 10.3389/fcvm.2021.796254. eCollection 2021.
Lysosomal dysfunction has been found in many pathological conditions, and methods to improve lysosomal function have been reported to be protective against infarcted hearts. However, the mechanisms underlying lysosomal dysfunction caused by ischemic injury are far less well-established. The retromer complex is implicated in the trafficking of cation-independent mannose 6-phosphate receptor (CI-MPR), which is an important protein tag for the proper transport of lysosomal contents and therefore is important for the maintenance of lysosomal function. In this study, we found that the function of retrograde transport in cardiomyocytes was impaired with ischemia/hypoxia (I/H) treatment, which resulted in a decrease in CI-MPR and an abnormal distribution of lysosomal cathepsins. I/H treatment caused a reduction in TBC1D5 and a blockade of the Rab7 membrane cycle, which impeded retromer binding to microtubules and motor proteins, resulting in an impairment of retrograde transport and a decrease in CI-MPR. We also established that TBC1D5 was an important regulator of the distribution of lysosomal cathepsins. Our findings shed light on the regulatory role of retromer in ischemic injury and uncover the regulatory mechanism of TBC1D5 over retromer.
溶酶体功能障碍在许多病理状况中都有发现，并且据报道改善溶酶体功能的方法对梗死心脏具有保护作用。然而，由缺血性损伤引起的溶酶体功能障碍的潜在机制仍远未明确。分拣连接蛋白复合物与不依赖阳离子的甘露糖6-磷酸受体（CI-MPR）的转运有关，CI-MPR是溶酶体内容物正常转运的重要蛋白质标签，因此对维持溶酶体功能很重要。在本研究中，我们发现缺血/缺氧（I/H）处理会损害心肌细胞中的逆向转运功能，这导致CI-MPR减少以及溶酶体组织蛋白酶分布异常。I/H处理导致TBC1D5减少并阻断Rab7膜循环，从而阻碍分拣连接蛋白复合物与微管和马达蛋白结合，导致逆向转运受损和CI-MPR减少。我们还确定TBC1D5是溶酶体组织蛋白酶分布的重要调节因子。我们的研究结果揭示了分拣连接蛋白复合物在缺血性损伤中的调节作用，并揭示了TBC1D5对分拣连接蛋白复合物的调节机制。
