Discovery of Hippo signaling as a regulator of CSPG4 expression and as a therapeutic target for Clostridioides difficile disease.
The signaling pathways and networks regulating expression of chondroitin sulfate proteoglycan 4 (CSPG4), a cancer-related protein that serves as a receptor for Clostridiodes difficile TcdB, are poorly defined. In this study, TcdB-resistant/CSPG4-negative HeLa cells were generated by exposure to incr...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-03-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1011272 |
| _version_ | 1797848148824031232 |
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| author | Jason L Larabee D Annie Doyle Ummey Khalecha Bintha Ahmed Tyler M Shadid Rachel R Sharp Kenneth L Jones Young Mi Kim Shibo Li Jimmy D Ballard |
| author_facet | Jason L Larabee D Annie Doyle Ummey Khalecha Bintha Ahmed Tyler M Shadid Rachel R Sharp Kenneth L Jones Young Mi Kim Shibo Li Jimmy D Ballard |
| author_sort | Jason L Larabee |
| collection | DOAJ |
| description | The signaling pathways and networks regulating expression of chondroitin sulfate proteoglycan 4 (CSPG4), a cancer-related protein that serves as a receptor for Clostridiodes difficile TcdB, are poorly defined. In this study, TcdB-resistant/CSPG4-negative HeLa cells were generated by exposure to increasing concentrations of the toxin. The cells that emerged (HeLa R5) lost expression of CSPG4 mRNA and were resistant to binding by TcdB. mRNA expression profiles paired with integrated pathway analysis correlated changes in the Hippo and estrogen signaling pathways with a CSPG4 decrease in HeLa R5 cells. Both signaling pathways altered CSPG4 expression when modulated chemically or through CRISPR-mediated deletion of key transcriptional regulators in the Hippo pathway. Based on the in vitro findings, we predicted and experimentally confirmed that a Hippo pathway inactivating drug (XMU-MP-1) provides protection from C. difficile disease in a mouse model. These results provide insights into key regulators of CSPG4 expression and identify a therapeutic for C. difficile disease. |
| first_indexed | 2024-04-09T18:22:47Z |
| format | Article |
| id | doaj.art-037c0a9f132e4f11a5b79a6fcfaa4202 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-09T18:22:47Z |
| publishDate | 2023-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-037c0a9f132e4f11a5b79a6fcfaa42022023-04-12T05:31:36ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742023-03-01193e101127210.1371/journal.ppat.1011272Discovery of Hippo signaling as a regulator of CSPG4 expression and as a therapeutic target for Clostridioides difficile disease.Jason L LarabeeD Annie DoyleUmmey Khalecha Bintha AhmedTyler M ShadidRachel R SharpKenneth L JonesYoung Mi KimShibo LiJimmy D BallardThe signaling pathways and networks regulating expression of chondroitin sulfate proteoglycan 4 (CSPG4), a cancer-related protein that serves as a receptor for Clostridiodes difficile TcdB, are poorly defined. In this study, TcdB-resistant/CSPG4-negative HeLa cells were generated by exposure to increasing concentrations of the toxin. The cells that emerged (HeLa R5) lost expression of CSPG4 mRNA and were resistant to binding by TcdB. mRNA expression profiles paired with integrated pathway analysis correlated changes in the Hippo and estrogen signaling pathways with a CSPG4 decrease in HeLa R5 cells. Both signaling pathways altered CSPG4 expression when modulated chemically or through CRISPR-mediated deletion of key transcriptional regulators in the Hippo pathway. Based on the in vitro findings, we predicted and experimentally confirmed that a Hippo pathway inactivating drug (XMU-MP-1) provides protection from C. difficile disease in a mouse model. These results provide insights into key regulators of CSPG4 expression and identify a therapeutic for C. difficile disease.https://doi.org/10.1371/journal.ppat.1011272 |
| spellingShingle | Jason L Larabee D Annie Doyle Ummey Khalecha Bintha Ahmed Tyler M Shadid Rachel R Sharp Kenneth L Jones Young Mi Kim Shibo Li Jimmy D Ballard Discovery of Hippo signaling as a regulator of CSPG4 expression and as a therapeutic target for Clostridioides difficile disease. PLoS Pathogens |
| title | Discovery of Hippo signaling as a regulator of CSPG4 expression and as a therapeutic target for Clostridioides difficile disease. |
| title_full | Discovery of Hippo signaling as a regulator of CSPG4 expression and as a therapeutic target for Clostridioides difficile disease. |
| title_fullStr | Discovery of Hippo signaling as a regulator of CSPG4 expression and as a therapeutic target for Clostridioides difficile disease. |
| title_full_unstemmed | Discovery of Hippo signaling as a regulator of CSPG4 expression and as a therapeutic target for Clostridioides difficile disease. |
| title_short | Discovery of Hippo signaling as a regulator of CSPG4 expression and as a therapeutic target for Clostridioides difficile disease. |
| title_sort | discovery of hippo signaling as a regulator of cspg4 expression and as a therapeutic target for clostridioides difficile disease |
| url | https://doi.org/10.1371/journal.ppat.1011272 |
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