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高血糖诱导组织蛋白酶 L 成熟与糖尿病合并症和 COVID-19 死亡率相关。

Hyperglycemia induced cathepsin L maturation linked to diabetic comorbidities and COVID-19 mortality.

机构信息

Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

Department of Respiratory and Critical Care Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

出版信息

Elife. 2024 Aug 16;13:RP92826. doi: 10.7554/eLife.92826.

DOI:10.7554/eLife.92826
PMID:39150053
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11329274/
Abstract

Diabetes, a prevalent chronic condition, significantly increases the risk of mortality from COVID-19, yet the underlying mechanisms remain elusive. Emerging evidence implicates Cathepsin L (CTSL) in diabetic complications, including nephropathy and retinopathy. Our previous research identified CTSL as a pivotal protease promoting SARS-CoV-2 infection. Here, we demonstrate elevated blood CTSL levels in individuals with diabetes, facilitating SARS-CoV-2 infection. Chronic hyperglycemia correlates positively with CTSL concentration and activity in diabetic patients, while acute hyperglycemia augments CTSL activity in healthy individuals. In vitro studies reveal high glucose, but not insulin, promotes SARS-CoV-2 infection in wild-type cells, with knockout cells displaying reduced susceptibility. Utilizing lung tissue samples from diabetic and non-diabetic patients, alongside mice and mice, we illustrate increased CTSL activity in both humans and mice under diabetic conditions. Mechanistically, high glucose levels promote CTSL maturation and translocation from the endoplasmic reticulum (ER) to the lysosome via the ER-Golgi-lysosome axis. Our findings underscore the pivotal role of hyperglycemia-induced CTSL maturation in diabetic comorbidities and complications.

摘要

糖尿病是一种常见的慢性疾病，会显著增加 COVID-19 死亡的风险，但潜在的机制仍不清楚。新出现的证据表明组织蛋白酶 L（CTSL）在糖尿病并发症中起作用，包括肾病和视网膜病变。我们之前的研究表明 CTSL 是促进 SARS-CoV-2 感染的关键蛋白酶。在这里，我们证明了糖尿病患者血液中的 CTSL 水平升高，促进了 SARS-CoV-2 的感染。慢性高血糖与糖尿病患者的 CTSL 浓度和活性呈正相关，而急性高血糖会增加健康个体的 CTSL 活性。体外研究表明，高葡萄糖而不是胰岛素促进野生型细胞中的 SARS-CoV-2 感染，而 knockout 细胞显示出较低的易感性。利用来自糖尿病和非糖尿病患者的肺组织样本以及小鼠和小鼠，我们表明在糖尿病条件下，人和小鼠的 CTSL 活性均增加。从机制上讲，高葡萄糖水平通过内质网-高尔基体-溶酶体轴促进 CTSL 的成熟和从内质网向溶酶体的易位。我们的发现强调了高血糖诱导的 CTSL 成熟在糖尿病合并症和并发症中的关键作用。

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Cathepsin D Drives the Formation of Hybrid Insulin Peptides Relevant to the Pathogenesis of Type 1 Diabetes.组织蛋白酶 D 驱动与 1 型糖尿病发病机制相关的杂交胰岛素肽的形成。
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Cell Commun Signal. 2025 Apr 24;23(1):198. doi: 10.1186/s12964-025-02205-z.
在新冠病毒刺突蛋白中鉴定出的新型切割位点揭示了组织蛋白酶L促进病毒感染的机制及治疗策略。
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