Soluble ACE2-mediated cell entry of SARS-CoV-2 via interaction with proteins related to the renin-angiotensin system

Cell. 2021 Apr 15;184(8):2212-2228.e12. doi: 10.1016/j.cell.2021.02.053. Epub 2021 Mar 2.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause acute respiratory disease and multiorgan failure. Finding human host factors that are essential for SARS-CoV-2 infection could facilitate the formulation of treatment strategies. Using a human kidney cell line-HK-2-that is highly susceptible to SARS-CoV-2, we performed a genome-wide RNAi screen and identified virus dependency factors (VDFs), which play regulatory roles in biological pathways linked to clinical manifestations of SARS-CoV-2 infection. We found a role for a secretory form of SARS-CoV-2 receptor, soluble angiotensin converting enzyme 2 (sACE2), in SARS-CoV-2 infection. Further investigation revealed that SARS-CoV-2 exploits receptor-mediated endocytosis through interaction between its spike with sACE2 or sACE2-vasopressin via AT1 or AVPR1B, respectively. Our identification of VDFs and the regulatory effect of sACE2 on SARS-CoV-2 infection shed insight into pathogenesis and cell entry mechanisms of SARS-CoV-2 as well as potential treatment strategies for COVID-19.

Keywords: ACE2; COVID-19; RNAi; SARS-CoV-2; sACE2; vasopressin; virus dependency factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2 / immunology*
  • COVID-19 / immunology
  • COVID-19 / virology
  • Cell Line
  • Host Microbial Interactions / immunology*
  • Humans
  • Protein Binding
  • SARS-CoV-2 / immunology*
  • Spike Glycoprotein, Coronavirus / immunology*
  • Vasopressins / immunology*
  • Virus Internalization*


  • Spike Glycoprotein, Coronavirus
  • spike protein, SARS-CoV-2
  • Vasopressins
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2