TY - JOUR
T1 - Proteomic Identification of Potential Target Proteins of Cathepsin W for Its Development as a Drug Target for Influenza
AU - Günther, Sira C.
AU - Martínez-Romero, Carles
AU - Borau, Milagros Sempere
AU - Pham, Christine T.N.
AU - García-Sastre, Adolfo
AU - Stertz, Silke
N1 - Funding Information:
The A.G.-S. laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories, and Merck, outside the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, Paratus, CureLab Oncology, CureLab Veterinary, Synairgen, and Pfizer, outside the reported work. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and Astra Zeneca. A.G.-S. is an inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer owned by the Icahn School of Medicine at Mount Sinai, New York, NY, outside the reported work.
Funding Information:
This work was funded by the Swiss National Science Foundation (grant no. 31003A_176170 to S.S.). This work was also partly funded by CRIPT (Center for Research in Influenza Response and Transmission), an NIAID funded Center of Excellence for Influenza Research and Response (CEIRR) (contract no. 75N93021C00014), and by NIAID grant no. U19 AI135972 to A.G.-S.
Funding Information:
This work was funded by the Swiss National Science Foundation (grant no. 31003A_176170 to S.S.). This work was also partly funded by CRIPT (Center for Research in Influenza Response and Transmission), an NIAID funded Center of Excellence for Influenza Research and Response (CEIRR) (contract no. 75N93021C00014), and by NIAID grant no. U19 AI135972 to A.G.-S. TAILS was performed with support of the Functional Genomics Center Zurich (FGCZ). Imaging was performed with support of the Center for Microscopy and Image Analysis, University of Zurich. The A.G.-S. laboratory has received research support from Pfizer, Senhwa Biosciences, Kenall Manufacturing, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories, and Merck, outside the reported work. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Vaxalto, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, Paratus, CureLab Oncology, CureLab Veterinary, Synairgen, and Pfizer, outside the reported work. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and Astra Zeneca. A.G.-S. is an inventor on patents and patent applications on the use of antivirals and vaccines for the treatment and prevention of virus infections and cancer owned by the Icahn School of Medicine at Mount Sinai, New York, NY, outside the reported work.
Publisher Copyright:
© 2022 Günther et al.
PY - 2022/8
Y1 - 2022/8
N2 - Influenza A virus (IAV) coopts numerous host factors for efficient replication. The cysteine protease cathepsin W (CTSW) has been identified as one host factor required for IAV entry, specifically for the escape of IAVs from late endosomes. However, the substrate specificity of CTSW and the proviral mechanism are thus far unknown. Here, we show that intracellular but not secreted CTSW promotes viral entry. We reveal 79 potential direct and 31 potential indirect cellular target proteins of CTSW using the high-throughput proteomic approach terminal amine isotopic labeling of substrates (TAILS) and determine the cleavage motif shared by the substrates of CTSW. Subsequent integration with data from RNA interference (RNAi) screens for IAV host factors uncovers first insights into the proviral function of CTSW. Notably, CTSW-deficient mice display a 25% increase in survival and a delay in mortality compared to wild-type mice upon IAV infection. Altogether, these findings support the development of drugs targeting CTSW as novel host-directed antiviral therapies.
AB - Influenza A virus (IAV) coopts numerous host factors for efficient replication. The cysteine protease cathepsin W (CTSW) has been identified as one host factor required for IAV entry, specifically for the escape of IAVs from late endosomes. However, the substrate specificity of CTSW and the proviral mechanism are thus far unknown. Here, we show that intracellular but not secreted CTSW promotes viral entry. We reveal 79 potential direct and 31 potential indirect cellular target proteins of CTSW using the high-throughput proteomic approach terminal amine isotopic labeling of substrates (TAILS) and determine the cleavage motif shared by the substrates of CTSW. Subsequent integration with data from RNA interference (RNAi) screens for IAV host factors uncovers first insights into the proviral function of CTSW. Notably, CTSW-deficient mice display a 25% increase in survival and a delay in mortality compared to wild-type mice upon IAV infection. Altogether, these findings support the development of drugs targeting CTSW as novel host-directed antiviral therapies.
KW - CTSW
KW - EPN2
KW - TAILS
KW - cathepsin W
KW - cysteine protease cathepsin W
KW - epsin 2
KW - host-directed antivirals
KW - influenza A virus
KW - influenza virus
KW - terminal amine isotopic labeling of substrates
KW - virus entry
UR - http://www.scopus.com/inward/record.url?scp=85137136403&partnerID=8YFLogxK
U2 - 10.1128/spectrum.00921-22
DO - 10.1128/spectrum.00921-22
M3 - Article
C2 - 35867415
AN - SCOPUS:85137136403
SN - 2165-0497
VL - 10
JO - Microbiology Spectrum
JF - Microbiology Spectrum
IS - 4
ER -