Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation
Identifieur interne : 000700 ( Pmc/Curation ); précédent : 000699; suivant : 000701Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation
Auteurs : Tommy Weiss-Sadan ; Gal Itzhak ; Farnusch Kaschani [Allemagne] ; Zhanru Yu [Royaume-Uni] ; Mohamed Mahameed ; Adi Anaki ; Yael Ben-Nun ; Emmanuelle Merquiol ; Boaz Tirosh ; Benedikt Kessler [Royaume-Uni] ; Markus Kaiser [Allemagne] ; Galia BlumSource :
- Molecular & Cellular Proteomics : MCP [ 1535-9476 ] ; 2019.
Abstract
Remodeling of cellular metabolism is a genuine feature of rapidly growing cells. Herein we report that mouse embryonic fibroblasts, lacking the Cathepsin L (Cts L) gene, proliferate faster than wild-types and display a noticeable glycolytic shift to satisfy their ever-growing metabolic needs. Mass spectrometry analyses identified LDHA as an essential metabolic junction in these cells, and downstream biochemical studies suggested that Cts L regulates LDHA expression and function. Together, these data uncover an unprecedented role for Cathepsin L in cell metabolism.
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DOI: 10.1074/mcp.RA119.001392
PubMed: 31010818
PubMed Central: 6601214
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Tommy Weiss-Sadan<affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation>Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation<xref ref-type="fn" rid="FN1"><sup><inline-graphic xlink:href="sbox.jpg"></inline-graphic></sup></xref></title><author><name sortKey="Weiss Sadan, Tommy" sort="Weiss Sadan, Tommy" uniqKey="Weiss Sadan T" first="Tommy" last="Weiss-Sadan">Tommy Weiss-Sadan</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Itzhak, Gal" sort="Itzhak, Gal" uniqKey="Itzhak G" first="Gal" last="Itzhak">Gal Itzhak</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Kaschani, Farnusch" sort="Kaschani, Farnusch" uniqKey="Kaschani F" first="Farnusch" last="Kaschani">Farnusch Kaschani</name><affiliation wicri:level="1"><nlm:aff id="aff2">§Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology, Faculty of Biology, Essen, Germany;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>§Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology, Faculty of Biology, Essen</wicri:regionArea></affiliation></author><author><name sortKey="Yu, Zhanru" sort="Yu, Zhanru" uniqKey="Yu Z" first="Zhanru" last="Yu">Zhanru Yu</name><affiliation wicri:level="1"><nlm:aff id="aff3">¶Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>¶Target Discovery Institute, Nuffield Department of 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id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Merquiol, Emmanuelle" sort="Merquiol, Emmanuelle" uniqKey="Merquiol E" first="Emmanuelle" last="Merquiol">Emmanuelle Merquiol</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Tirosh, Boaz" sort="Tirosh, Boaz" uniqKey="Tirosh B" first="Boaz" last="Tirosh">Boaz Tirosh</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Kessler, Benedikt" sort="Kessler, Benedikt" uniqKey="Kessler B" first="Benedikt" last="Kessler">Benedikt Kessler</name><affiliation wicri:level="1"><nlm:aff id="aff3">¶Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>¶Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford</wicri:regionArea></affiliation></author><author><name sortKey="Kaiser, Markus" sort="Kaiser, Markus" uniqKey="Kaiser M" first="Markus" last="Kaiser">Markus Kaiser</name><affiliation wicri:level="1"><nlm:aff id="aff2">§Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology, Faculty of Biology, Essen, Germany;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>§Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology, Faculty of Biology, Essen</wicri:regionArea></affiliation></author><author><name sortKey="Blum, Galia" sort="Blum, Galia" uniqKey="Blum G" first="Galia" last="Blum">Galia Blum</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31010818</idno><idno type="pmc">6601214</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601214</idno><idno type="RBID">PMC:6601214</idno><idno type="doi">10.1074/mcp.RA119.001392</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000700</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000700</idno><idno type="wicri:Area/Pmc/Curation">000700</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000700</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation<xref ref-type="fn" rid="FN1"><sup><inline-graphic xlink:href="sbox.jpg"></inline-graphic></sup></xref></title><author><name sortKey="Weiss Sadan, Tommy" sort="Weiss Sadan, Tommy" uniqKey="Weiss Sadan T" first="Tommy" last="Weiss-Sadan">Tommy Weiss-Sadan</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Itzhak, Gal" sort="Itzhak, Gal" uniqKey="Itzhak G" first="Gal" last="Itzhak">Gal Itzhak</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Kaschani, Farnusch" sort="Kaschani, Farnusch" uniqKey="Kaschani F" first="Farnusch" last="Kaschani">Farnusch Kaschani</name><affiliation wicri:level="1"><nlm:aff id="aff2">§Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology, Faculty of Biology, Essen, Germany;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>§Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology, Faculty of Biology, Essen</wicri:regionArea></affiliation></author><author><name sortKey="Yu, Zhanru" sort="Yu, Zhanru" uniqKey="Yu Z" first="Zhanru" last="Yu">Zhanru Yu</name><affiliation wicri:level="1"><nlm:aff id="aff3">¶Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>¶Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford</wicri:regionArea></affiliation></author><author><name sortKey="Mahameed, Mohamed" sort="Mahameed, Mohamed" uniqKey="Mahameed M" first="Mohamed" last="Mahameed">Mohamed Mahameed</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Anaki, Adi" sort="Anaki, Adi" uniqKey="Anaki A" first="Adi" last="Anaki">Adi Anaki</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Ben Nun, Yael" sort="Ben Nun, Yael" uniqKey="Ben Nun Y" first="Yael" last="Ben-Nun">Yael Ben-Nun</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Merquiol, Emmanuelle" sort="Merquiol, Emmanuelle" uniqKey="Merquiol E" first="Emmanuelle" last="Merquiol">Emmanuelle Merquiol</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Tirosh, Boaz" sort="Tirosh, Boaz" uniqKey="Tirosh B" first="Boaz" last="Tirosh">Boaz Tirosh</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author><author><name sortKey="Kessler, Benedikt" sort="Kessler, Benedikt" uniqKey="Kessler B" first="Benedikt" last="Kessler">Benedikt Kessler</name><affiliation wicri:level="1"><nlm:aff id="aff3">¶Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK</nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>¶Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford</wicri:regionArea></affiliation></author><author><name sortKey="Kaiser, Markus" sort="Kaiser, Markus" uniqKey="Kaiser M" first="Markus" last="Kaiser">Markus Kaiser</name><affiliation wicri:level="1"><nlm:aff id="aff2">§Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology, Faculty of Biology, Essen, Germany;</nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>§Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology, Faculty of Biology, Essen</wicri:regionArea></affiliation></author><author><name sortKey="Blum, Galia" sort="Blum, Galia" uniqKey="Blum G" first="Galia" last="Blum">Galia Blum</name><affiliation><nlm:aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</nlm:aff><wicri:noCountry code="subfield">9112001</wicri:noCountry></affiliation></author></analytic><series><title level="j">Molecular & Cellular Proteomics : MCP</title><idno type="ISSN">1535-9476</idno><idno type="eISSN">1535-9484</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Remodeling of cellular metabolism is a genuine feature of rapidly growing cells. Herein we report that mouse embryonic fibroblasts, lacking the Cathepsin L (Cts L) gene, proliferate faster than wild-types and display a noticeable glycolytic shift to satisfy their ever-growing metabolic needs. Mass spectrometry analyses identified LDHA as an essential metabolic junction in these cells, and downstream biochemical studies suggested that Cts L regulates LDHA expression and function. Together, these data uncover an unprecedented role for Cathepsin L in cell metabolism.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lunt, S Y" uniqKey="Lunt S">S. Y. Lunt</name></author><author><name sortKey="Vander Heiden, M G" uniqKey="Vander Heiden M">M. G. Vander Heiden</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Deberardinis, R J" uniqKey="Deberardinis R">R. J. DeBerardinis</name></author><author><name sortKey="Lum, J J" uniqKey="Lum J">J. J. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Mol Cell Proteomics</journal-id><journal-id journal-id-type="iso-abbrev">Mol. Cell Proteomics</journal-id><journal-id journal-id-type="hwp">mcprot</journal-id><journal-id journal-id-type="pmc">mcprot</journal-id><journal-id journal-id-type="publisher-id">MCP</journal-id><journal-title-group><journal-title>Molecular & Cellular Proteomics : MCP</journal-title></journal-title-group><issn pub-type="ppub">1535-9476</issn><issn pub-type="epub">1535-9484</issn><publisher><publisher-name>The American Society for Biochemistry and Molecular Biology</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31010818</article-id><article-id pub-id-type="pmc">6601214</article-id><article-id pub-id-type="publisher-id">RA119.001392</article-id><article-id pub-id-type="doi">10.1074/mcp.RA119.001392</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research</subject></subj-group></article-categories><title-group><article-title>Cathepsin L Regulates Metabolic Networks Controlling Rapid Cell Growth and Proliferation<xref ref-type="fn" rid="FN1"><sup><inline-graphic xlink:href="sbox.jpg"></inline-graphic></sup></xref></article-title><alt-title alt-title-type="short">Cts L Regulates Glycolytic Metabolism to Control Cell Growth</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Weiss-Sadan</surname><given-names>Tommy</given-names></name><xref ref-type="aff" rid="aff1">‡</xref></contrib><contrib contrib-type="author"><name><surname>Itzhak</surname><given-names>Gal</given-names></name><xref ref-type="aff" rid="aff1">‡</xref></contrib><contrib contrib-type="author"><name><surname>Kaschani</surname><given-names>Farnusch</given-names></name><xref ref-type="aff" rid="aff2">§</xref></contrib><contrib contrib-type="author"><name><surname>Yu</surname><given-names>Zhanru</given-names></name><xref ref-type="aff" rid="aff3">¶</xref></contrib><contrib contrib-type="author"><name><surname>Mahameed</surname><given-names>Mohamed</given-names></name><xref ref-type="aff" rid="aff1">‡</xref></contrib><contrib contrib-type="author"><name><surname>Anaki</surname><given-names>Adi</given-names></name><xref ref-type="aff" rid="aff1">‡</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-5123-649X</contrib-id><name><surname>Ben-Nun</surname><given-names>Yael</given-names></name><xref ref-type="aff" rid="aff1">‡</xref></contrib><contrib contrib-type="author"><name><surname>Merquiol</surname><given-names>Emmanuelle</given-names></name><xref ref-type="aff" rid="aff1">‡</xref></contrib><contrib contrib-type="author"><name><surname>Tirosh</surname><given-names>Boaz</given-names></name><xref ref-type="aff" rid="aff1">‡</xref></contrib><contrib contrib-type="author"><name><surname>Kessler</surname><given-names>Benedikt</given-names></name><xref ref-type="aff" rid="aff3">¶</xref></contrib><contrib contrib-type="author"><name><surname>Kaiser</surname><given-names>Markus</given-names></name><xref ref-type="aff" rid="aff2">§</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">https://orcid.org/0000-0002-9374-2489</contrib-id><name><surname>Blum</surname><given-names>Galia</given-names></name><xref ref-type="aff" rid="aff1">‡</xref><xref ref-type="corresp" rid="cor1">‖</xref></contrib><aff id="aff1">From the ‡Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001;</aff><aff id="aff2">§Department of Chemical Biology, University of Duisburg-Essen, Center for Medical Biotechnology, Faculty of Biology, Essen, Germany;</aff><aff id="aff3">¶Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, UK</aff></contrib-group><author-notes><corresp id="cor1">‖ To whom correspondence should be addressed:
<addr-line>Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University, Jerusalem, Israel, 9112001.</addr-line> E-mail:
<email>galiabl@ekmd.huji.ac.il</email>.</corresp><fn fn-type="con"><p>Author contributions: T.W.S., G.I., B.K., and G.B. designed research; T.W.S., G.I., F.K., Z.Y., M.M., A.A., E.M., and G.B. performed research; T.W.S., G.I., F.K., Z.Y., M.M., A.A., Y.B.-N., E.M., B.T., B.K., and G.B. analyzed data; T.W.S., G.I., F.K., Z.Y., B.T., B.K., M.K., and G.B. wrote the paper; F.K., Z.Y., M.M., Y.B.-N., B.T., B.K., and M.K. contributed new reagents/analytic tools.</p></fn></author-notes><pub-date pub-type="ppub"><month>7</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>22</day><month>4</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>22</day><month>4</month><year>2019</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>18</volume><issue>7</issue><fpage>1330</fpage><lpage>1344</lpage><history><date date-type="received"><day>18</day><month>2</month><year>2019</year></date><date date-type="rev-recd"><day>7</day><month>4</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 Weiss-Sadan et al.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Weiss-Sadan et al.</copyright-holder><license><license-p>Published by The American Society for Biochemistry and Molecular Biology, Inc.</license-p></license><license license-type="open-access"><license-p><italic>Author's Choice</italic>—Final version open access under the terms of the <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0">Creative Commons CC-BY license</ext-link>.</license-p></license></permissions><self-uri content-type="pdf" xlink:href="zjw0071959481329.pdf"></self-uri><abstract abstract-type="precis"><p>Remodeling of cellular metabolism is a genuine feature of rapidly growing cells. Herein we report that mouse embryonic fibroblasts, lacking the Cathepsin L (Cts L) gene, proliferate faster than wild-types and display a noticeable glycolytic shift to satisfy their ever-growing metabolic needs. Mass spectrometry analyses identified LDHA as an essential metabolic junction in these cells, and downstream biochemical studies suggested that Cts L regulates LDHA expression and function. Together, these data uncover an unprecedented role for Cathepsin L in cell metabolism.</p></abstract><abstract abstract-type="graphical"><title>Graphical Abstract</title><p><fig id="F7" fig-type="featured" orientation="portrait" position="float"><graphic xlink:href="zjw0071959480007"></graphic></fig></p><p><bold>Highlights</bold></p><p><list list-type="bullet"><list-item><p>Cts L<sup>−/−</sup> cells proliferate faster than wild types and shift to aerobic glycolysis.</p></list-item><list-item><p>LDHA is a key glycolytic enzyme controlling Cts L<sup>−/−</sup> cell proliferation.</p></list-item><list-item><p>Cts L regulates LDHA expression and function.</p></list-item></list></p></abstract><abstract><p>Rapidly proliferating cells reshape their metabolism to satisfy their ever-lasting need for cellular building blocks. This phenomenon is exemplified in certain malignant conditions such as cancer but also during embryonic development when cells rely heavily on glycolytic metabolism to exploit its metabolic intermediates for biosynthetic processes. How cells reshape their metabolism is not fully understood. Here we report that loss of cathepsin L (Cts L) is associated with a fast proliferation rate and enhanced glycolytic metabolism that depend on lactate dehydrogenase A (LDHA) activity. Using mass spectrometry analysis of cells treated with a pan cathepsin inhibitor, we observed an increased abundance of proteins involved in central carbon metabolism. Further inspection of putative Cts L targets revealed an enrichment for glycolytic metabolism that was independently confirmed by metabolomic and biochemical analyses. Moreover, proteomic analysis of Cts L-knockout cells identified LDHA overexpression that was demonstrated to be a key metabolic junction in these cells. Lastly, we show that Cts L inhibition led to increased LDHA protein expression, suggesting a causal relationship between LDHA expression and function. In conclusion, we propose that Cts L regulates this metabolic circuit to keep cell division under control, suggesting the therapeutic potential of targeting this protein and its networks in cancer.</p></abstract><kwd-group><kwd>Proteases*</kwd><kwd>Metabolomics</kwd><kwd>Gene Expression*</kwd><kwd>Pathway Analysis</kwd><kwd>Proteolysis*</kwd><kwd>Cathepsin L</kwd><kwd>Glycolysis</kwd><kwd>Proliferation</kwd></kwd-group><funding-group><award-group id="award1"><funding-source><institution-wrap><institution>United States - Israel Binational Science Foundation (BSF)</institution><institution-id>https://dx.doi.org/10.13039/100006221</institution-id></institution-wrap></funding-source><award-id>2009010</award-id><award-id>2011480</award-id><principal-award-recipient><name><surname>Blum</surname><given-names>Galia</given-names></name></principal-award-recipient></award-group><award-group id="award2"><funding-source><institution-wrap><institution>EC | FP7 | FP7 Ideas: European Research Council (FP7 Ideas)</institution><institution-id>https://dx.doi.org/10.13039/100011199</institution-id></institution-wrap></funding-source><award-id>337238</award-id><principal-award-recipient><name><surname>Blum</surname><given-names>Galia</given-names></name></principal-award-recipient></award-group></funding-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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