Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
Ming-Jia Li
Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
Xiao-Ya Li
Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
Jian-Min Jin
Department of Respiratory and Critical Care Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, China
Ying-Mei Feng
Department of Science and Technology, Beijing Youan Hospital, Capital Medical University, Beijing, China
Li Zhang
Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, China, Beijing, China
Wei Jin Huang
Division of HIV/AIDS and Sex-Transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC), Beijing, China, Beijing, China
Fangyuan Yang
Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China
Department of Endocrinology, Beijing Diabetes Institute, Beijing Tongren Hospital, Capital Medical University, Beijing, China; Laboratory for Clinical Medicine, Capital Medical University, Beijing, China
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 CTSL knockout cells displaying reduced susceptibility. Utilizing lung tissue samples from diabetic and non-diabetic patients, alongside Leprdb/dbmice and Leprdb/+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.
