TMPRSS2 Isoform 1 Activates Respiratory Viruses and Is Expressed in Viral Target Cells

PLoS One. 2015 Sep 17;10(9):e0138380. doi: 10.1371/journal.pone.0138380. eCollection 2015.

Abstract

The cellular protease TMPRSS2 cleaves and activates the influenza virus hemagglutinin (HA) and TMPRSS2 expression is essential for viral spread and pathogenesis in mice. Moreover, severe acute respiratory syndrome coronavirus (SARS-CoV) and other respiratory viruses are activated by TMPRSS2. However, previous studies on viral activation by TMPRSS2 focused on a 492 amino acids comprising form of the protein (isoform 2) while other TMPRSS2 isoforms, generated upon alternative splicing of the tmprss2 mRNA, have not been characterized. Here, we show that the mRNA encoding a TMPRSS2 isoform with an extended N-terminal cytoplasmic domain (isoform 1) is expressed in lung-derived cell lines and tissues. Moreover, we demonstrate that TMPRSS2 isoform 1 colocalizes with HA and cleaves and activates HA. Finally, we show that isoform 1 activates the SARS-CoV spike protein for cathepsin L-independent entry into target cells. Our results indicate that TMPRSS2 isoform 1 is expressed in viral target cells and might contribute to viral activation in the host.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Caco-2 Cells
  • Cathepsins / metabolism
  • Cell Line
  • Chlorocebus aethiops
  • HEK293 Cells
  • Hemagglutinins / metabolism
  • Host-Pathogen Interactions / physiology
  • Humans
  • Lung / metabolism
  • Lung / virology
  • Orthomyxoviridae / metabolism
  • Protein Isoforms / metabolism*
  • RNA, Messenger / metabolism
  • SARS Virus / metabolism*
  • Serine Endopeptidases / metabolism*
  • Spike Glycoprotein, Coronavirus / metabolism
  • Virus Internalization

Substances

  • Hemagglutinins
  • Protein Isoforms
  • RNA, Messenger
  • Spike Glycoprotein, Coronavirus
  • Cathepsins
  • Serine Endopeptidases
  • TMPRSS2 protein, human

Grant support

This work was supported by DFG (PO 716/6-1) and the Gӧttingen Graduate School for Neurosciences, Biophysics, and Molecular Biosciences (DFG Grant GSC 226/1 and DFG Grant GSC 226/2).