tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2022 Jan 25;119(4):e2117576119.
doi: 10.1073/pnas.2117576119.
SNX27 suppresses SARS-CoV-2 infection by inhibiting viral lysosome/late endosome entry
Bo Yang[SUP] 1 2 [/SUP], Yuanyuan Jia[SUP] 1 [/SUP], Yumin Meng[SUP] 3 [/SUP], Ying Xue[SUP] 1 [/SUP], Kefang Liu[SUP] 3 [/SUP], Yan Li[SUP] 3 [/SUP], Shichao Liu[SUP] 1 [/SUP], Xiaoxiong Li[SUP] 1 [/SUP], Kaige Cui[SUP] 1 [/SUP], Lina Shang[SUP] 1 [/SUP], Tianyou Cheng[SUP] 1 [/SUP], Zhichao Zhang[SUP] 1 [/SUP], Yingxiang Hou[SUP] 1 4 [/SUP], Xiaozhu Yang[SUP] 1 [/SUP], Hong Yan[SUP] 1 [/SUP], Liqiang Duan[SUP] 1 [/SUP], Zhou Tong[SUP] 1 3 [/SUP], Changxin Wu[SUP] 1 4 [/SUP], Zhida Liu[SUP] 1 [/SUP], Shan Gao[SUP] 1 [/SUP], Shu Zhuo[SUP] 5 [/SUP], Weijin Huang[SUP] 6 [/SUP], George Fu Gao[SUP] 7 3 [/SUP], Jianxun Qi[SUP] 8 [/SUP], Guijun Shang[SUP] 7 2 [/SUP]
Affiliations
Abstract
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.
Keywords: ACE2; RBD; SARS-CoV-2; SNX27; retromer.
. 2022 Jan 25;119(4):e2117576119.
doi: 10.1073/pnas.2117576119.
SNX27 suppresses SARS-CoV-2 infection by inhibiting viral lysosome/late endosome entry
Bo Yang[SUP] 1 2 [/SUP], Yuanyuan Jia[SUP] 1 [/SUP], Yumin Meng[SUP] 3 [/SUP], Ying Xue[SUP] 1 [/SUP], Kefang Liu[SUP] 3 [/SUP], Yan Li[SUP] 3 [/SUP], Shichao Liu[SUP] 1 [/SUP], Xiaoxiong Li[SUP] 1 [/SUP], Kaige Cui[SUP] 1 [/SUP], Lina Shang[SUP] 1 [/SUP], Tianyou Cheng[SUP] 1 [/SUP], Zhichao Zhang[SUP] 1 [/SUP], Yingxiang Hou[SUP] 1 4 [/SUP], Xiaozhu Yang[SUP] 1 [/SUP], Hong Yan[SUP] 1 [/SUP], Liqiang Duan[SUP] 1 [/SUP], Zhou Tong[SUP] 1 3 [/SUP], Changxin Wu[SUP] 1 4 [/SUP], Zhida Liu[SUP] 1 [/SUP], Shan Gao[SUP] 1 [/SUP], Shu Zhuo[SUP] 5 [/SUP], Weijin Huang[SUP] 6 [/SUP], George Fu Gao[SUP] 7 3 [/SUP], Jianxun Qi[SUP] 8 [/SUP], Guijun Shang[SUP] 7 2 [/SUP]
Affiliations
- PMID: 35022217
- DOI: 10.1073/pnas.2117576119
Abstract
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.
Keywords: ACE2; RBD; SARS-CoV-2; SNX27; retromer.