期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：4
DOI：10.1073/pnas.2117576119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
We here established the interaction between PDZ binding motif (PBM) at the C terminal of ACE2 and PDZ domain of sorting nexin 27 (SNX27) and solved the crystal structure of ACE2-PBM/SNX27-PDZ complex. Together with retromer complex, SNX27 was found to regulate the homeostasis of cell surface ACE2 under physiological conditions. When endocytic pathway was used during SARS-CoV-2 infection, SNX27-retromer sorts ACE2/SARS-CoV-2 complex at early endosome and prevents it from entering lysosome/late endosome, inhibiting the cell entry of the virus. These findings add substantially to the current understanding of the important role of cytosolic tail of ACE2 during the invasion of SARS-CoV-2, and it could be used as a new therapeutic target for drug development.
After binding to its cell surface receptor angiotensin converting enzyme 2 (ACE2), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters the host cell through directly fusing with plasma membrane (cell surface pathway) or undergoing endocytosis traveling to lysosome/late endosome for membrane fusion (endocytic pathway). However, the endocytic entry regulation by host cell remains elusive. Recent studies show ACE2 possesses a type I PDZ binding motif (PBM) through which it could interact with a PDZ domain-containing protein such as sorting nexin 27 (SNX27). In this study, we determined the ACE2-PBM/SNX27-PDZ complex structure, and, through a series of functional analyses, we found SNX27 plays an important role in regulating the homeostasis of ACE2 receptor. More importantly, we demonstrated SNX27, together with retromer complex (the core component of the endosomal protein sorting machinery), prevents ACE2/virus complex from entering lysosome/late endosome, resulting in decreased viral entry in cells where the endocytic pathway dominates. The ACE2/virus retrieval mediated by SNX27–retromer could be considered as a countermeasure against invasion of ACE2 receptor-using SARS coronaviruses.
