SARS coronavirus, but not human coronavirus NL63, utilizes cathepsin L to infect ACE2-expressing cells

J Biol Chem. 2006 Feb 10;281(6):3198-203. doi: 10.1074/jbc.M508381200. Epub 2005 Dec 8.


Viruses require specific cellular receptors to infect their target cells. Angiotensin-converting enzyme 2 (ACE2) is a cellular receptor for two divergent coronaviruses, SARS coronavirus (SARS-CoV) and human coronavirus NL63 (HCoV-NL63). In addition to hostcell receptors, lysosomal cysteine proteases are required for productive infection by some viruses. Here we show that SARS-CoV, but not HCoV-NL63, utilizes the enzymatic activity of the cysteine protease cathepsin L to infect ACE2-expressing cells. Inhibitors of cathepsin L blocked infection by SARS-CoV and by a retrovirus pseudotyped with the SARS-CoV spike (S) protein but not infection by HCoV-NL63 or a retrovirus pseudotyped with the HCoV-NL63 S protein. Expression of exogenous cathepsin L substantially enhanced infection mediated by the SARS-CoV S protein and by filovirus GP proteins but not by the HCoV-NL63 S protein or the vesicular stomatitis virus G protein. Finally, an inhibitor of endosomal acidification had substantially less effect on infection mediated by the HCoV-NL63 S protein than on that mediated by the SARS-CoV S protein. Our data indicate that two coronaviruses that utilize a common receptor nonetheless enter cells through distinct mechanisms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Carboxypeptidases / metabolism*
  • Cathepsin L
  • Cathepsins / metabolism
  • Cathepsins / physiology*
  • Cell Line
  • Chlorocebus aethiops
  • Coronavirus / physiology*
  • Cysteine Endopeptidases / metabolism
  • Cysteine Endopeptidases / physiology*
  • Endosomes / metabolism
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Lysosomes / enzymology
  • Membrane Glycoproteins / metabolism
  • Peptidyl-Dipeptidase A
  • Retroviridae / genetics
  • SARS Virus / physiology*
  • Species Specificity
  • Vero Cells
  • Viral Envelope Proteins / metabolism


  • G protein, vesicular stomatitis virus
  • Membrane Glycoproteins
  • Viral Envelope Proteins
  • Green Fluorescent Proteins
  • Carboxypeptidases
  • Cathepsins
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2
  • Cysteine Endopeptidases
  • CTSL protein, human
  • Cathepsin L