SNX27 suppresses SARS-CoV-2 infection by inhibiting viral lysosome/late endosome entry

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.

Inhibition of endocytic recycling of ACE2 by SARS-CoV-2 S protein partially explains multiple COVID-19 related diseases caused by ACE2 reduction

“…Consistent with our study, recent studies found that ACE2 surface localization was mediated by SNX27 and SARS-CoV-2 S associated with SNX27 ( 5 , 6 , 7 , 8 ). However, those studies did not explore the role for SARS-CoV-2 S in the endocytic recycling of ACE2.…”

The ACE2 Receptor for Coronavirus Entry Is Localized at Apical Cell—Cell Junctions of Epithelial Cells

“…Thus, a disruption of the scaffolding complexes that anchor ACE2 to the plasma membrane could facilitate endocytosis and virus entry. In agreement with this idea, it was recently reported that ACE2 interacts directly with the cytoplasmic PDZ proteins NHERF1 and SNX27, and these interactions modulate ACE2-mediated SARS-CoV-2 cell entry [ 82 , 83 ]. Interestingly, both NHERF1 and SNX27 also modulate TJ organization and barrier function, by associating with the TJ protein ZO-2 (SNX27) and regulating cytoskeletal organization and membrane trafficking [ 84 , 85 ].…”

ESCPE-1 mediates retrograde endosomal sorting of the SARS-CoV-2 host factor Neuropilin-1

“…Interestingly, additional pathogens hijack ESCPE-1 cargo recognition to promote intracellular survival (2,3,44), and SNX5 has also recently been identified as a key regulator of innate cellular immunity against a range of viruses (45). Genomewide CRISPR screens and biochemical studies have identified multiple endosomal sorting machineries that facilitate SARS-CoV-2 infection, including components of the retromer, retriever and COMMD/CCDC22/CCDC93 (CCC) complexes (46)(47)(48)(49)(50)(51). Here, we suggest that ESCPE-1 sequence-dependent cargo sorting also plays a role in regulating the endosomal dynamics exploited during SARS-CoV-2 infection, potentially expanding the scope of pathogens that can exploit this complex.…”