Facilitation of Autophagosome-Lysosome Fusion by LAPTM4A: A Novel Strategy for Attenuating Myocardial Ischemia-Reperfusion Injury
Abstract
BACKGROUND: Myocardial ischemia-reperfusion (MIR) injury compromises therapeutic effects of revascularization and leads to functional impairment and exacerbation of structural damage in the heart. Limiting the damage caused by MIR is crucial but is still an unmet clinical need because of the complexity of the underlying mechanisms. Increasing evidence suggests that lysosomal autophagy plays a significant regulatory role in MIR injury. The specific mechanisms involved remain to be fully understood. METHODS: We here systematically analyzed the murine MIR model database to screen the potentially protective lysosome-localized proteins against MIR injury. The positive hits were further functionally screened and validated for their capability on autophagy and hypoxia/reoxygenation insults of cardiomyocytes. After exploring the detailed molecular mechanism underlying the protective effects of the target protein, we generated target gene cardiac-specific knockout mice and overexpression mice to verify its function in mouse MIR injury models. RESULTS: LAPTM4A (lysosome-associated protein transmembrane 4 alpha) stood out as a significant protective lysosome-localized protein from the screening. LAPTM4A deficiency significantly heightened the inflammatory response and cell death both in primary cardiomyocytes and in a MIR-induced mouse model. Conversely, LAPTM4A overexpression exerted protective effects on cell viability and myocardial damage. Mechanistically, LAPTM4A interacts with Rubicon (Run domain Beclin1-interacting and cysteine-rich domain–containing protein), hindering its engagement within the Beclin1 complex, resulting in a robust augmentation of autophagic flux and thereby mitigating cardiac damage during reperfusion. It is important to note that Rubicon knockdown markedly reversed the aggravated injury induced by LAPTM4A knockdown, further verifying the effects of LAPTM4A depend on Rubicon. CONCLUSIONS: Our findings screened out and validated that LAPTM4A is a lysosome-localized protein exerting protective effects against MIR injury by facilitating autophagic flux. Targeting LAPTM4A represents a promising therapeutic strategy for mitigating MIR injury.
Article Details
Authors (30)
Siyi Zhou
Jiayi Liu
Manli Hu
State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, School of Pharmacy, First Affiliated Hospital, Gannan Medical University, Ganzhou, China (S.Z., M.H., S.T., J.Z., H.C., S.W., X. Zhou, X.C., Y.H., Z.S., L.B., H.Y., H. Liu, J. Wan, X.-J.Z., J.C., Z.-G.S., X. Zhang, H. Li).
Song Tian
Junjie Zhou
Wei Li
Hailian Chen
Maoji Yin
Department of Cardiology, Renmin Hospital, Wuhan University, China (J.L., W.L., M.Y., L.L., L.Z., Z.-G.S.).
Shiyi Wang
Lei Luo
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road 457, Dalian 116023, P. R. China
Long Zhang
Xiangqiang Zhou
State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, School of Pharmacy, First Affiliated Hospital, Gannan Medical University, Ganzhou, China (S.Z., M.H., S.T., J.Z., H.C., S.W., X. Zhou, X.C., Y.H., Z.S., L.B., H.Y., H. Liu, J. Wan, X.-J.Z., J.C., Z.-G.S., X. Zhang, H. Li).
Xu Cheng
QTF Center of Excellence, Department of Electronics and Nanoengineering
Quanqing Qiu
TargetHunter PharmaTech (Jiangxi) Co, Ltd, Ganzhou, China (X.C., Q.Q., J. Wang).
Jinsheng Wang
Weiyi Qu
Yufeng Hu
State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, School of Pharmacy, First Affiliated Hospital, Gannan Medical University, Ganzhou, China (S.Z., M.H., S.T., J.Z., H.C., S.W., X. Zhou, X.C., Y.H., Z.S., L.B., H.Y., H. Liu, J. Wan, X.-J.Z., J.C., Z.-G.S., X. Zhang, H. Li).
Péter Ferdinandy
Department of Pharmacology and Pharmacotherapy, Center for Pharmacology and Drug Development, Semmelweis University, Budapest, Hungary (P.F.).
Mario Chiong
Advanced Center for Chronic Diseases, Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago (M.C., M.F.T.).
Mayarling F. Troncoso
Advanced Center for Chronic Diseases, Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago (M.C., M.F.T.).
Zhaoliang Shan
Lan Bai
State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, School of Pharmacy, First Affiliated Hospital, Gannan Medical University, Ganzhou, China (S.Z., M.H., S.T., J.Z., H.C., S.W., X. Zhou, X.C., Y.H., Z.S., L.B., H.Y., H. Liu, J. Wan, X.-J.Z., J.C., Z.-G.S., X. Zhang, H. Li).
Hailong Yang
Hui Liu
Juan Wan
Xiao-Jing Zhang
Jingjing Cai
Zhi-Gang She
Xin Zhang
Hongliang Li
Hefei National Research Center for Physical Sciences at the Microscale