title: TMPRSS2 Isoform 1 Activates Respiratory Viruses and Is Expressed in Viral Target Cells.
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.
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Pawel
authors.initials: P
authors.lastname: Zmora
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Anna-Sophie
authors.initials: AS
authors.lastname: Moldenhauer
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Hofmann-Winkler
authors.affiliation: Infection Biology Unit, German Primate Center, Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Pöhlmann
mesh_terms: D000818:Animals; D019556:COS Cells; D018938:Caco-2 Cells; D002403:Cathepsins / Q000378:metabolism; D002460:Cell Line; D002522:Chlorocebus aethiops; D057809:HEK293 Cells; D006388:Hemagglutinins / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000502:physiology; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000821:virology; D009975:Orthomyxoviridae / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D045473:Severe acute respiratory syndrome-related coronavirus / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D064370:Spike Glycoprotein, Coronavirus / Q000378:metabolism; D053586:Virus Internalization
chemical_list: D006388:Hemagglutinins; D020033:Protein Isoforms; D012333:RNA, Messenger; D064370:Spike Glycoprotein, Coronavirus; D002403:Cathepsins; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human