Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12
<p dir="ltr">Transforming growth factor β (TGFβ) pathway is a master regulator of cell proliferation, differentiation, and death. Deregulation of TGFβ signalling is well established in several human diseases including autoimmune disorders and cancer. Thus, understanding molecular pat...
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| مؤلفون آخرون: | , , , , , , , , , , , , , , |
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2023
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| _version_ | 1864513507577298944 |
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| author | Kripa S Keyan (10644815) |
| author2 | Safa Salim (9186786) Swetha Gowda (19459546) Doua Abdelrahman (17280667) Syeda Sakina Amir (19459549) Zeyaul Islam (5867387) Claire Vargas (19459552) Maria Teresa Bengoechea-Alonso (2936889) Amira Alwa (11438828) Subrat Dahal (19459555) Prasanna R. Kolatkar (124118) Sahar Da’as (15430086) Jerome Torrisani (19459558) Johan Ericsson (49714) Farhan Mohammad (256409) Omar M Khan (9260654) |
| author2_role | author author author author author author author author author author author author author author author |
| author_facet | Kripa S Keyan (10644815) Safa Salim (9186786) Swetha Gowda (19459546) Doua Abdelrahman (17280667) Syeda Sakina Amir (19459549) Zeyaul Islam (5867387) Claire Vargas (19459552) Maria Teresa Bengoechea-Alonso (2936889) Amira Alwa (11438828) Subrat Dahal (19459555) Prasanna R. Kolatkar (124118) Sahar Da’as (15430086) Jerome Torrisani (19459558) Johan Ericsson (49714) Farhan Mohammad (256409) Omar M Khan (9260654) |
| author_role | author |
| dc.creator.none.fl_str_mv | Kripa S Keyan (10644815) Safa Salim (9186786) Swetha Gowda (19459546) Doua Abdelrahman (17280667) Syeda Sakina Amir (19459549) Zeyaul Islam (5867387) Claire Vargas (19459552) Maria Teresa Bengoechea-Alonso (2936889) Amira Alwa (11438828) Subrat Dahal (19459555) Prasanna R. Kolatkar (124118) Sahar Da’as (15430086) Jerome Torrisani (19459558) Johan Ericsson (49714) Farhan Mohammad (256409) Omar M Khan (9260654) |
| dc.date.none.fl_str_mv | 2023-10-20T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41419-023-06215-y |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Control_of_TGF_signalling_by_ubiquitination_independent_function_of_E3_ubiquitin_ligase_TRIP12/26798146 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Immunology Oncology and carcinogenesis Cell Proliferation Cell Differentiation Cell Death Genetic Inhibition Evolutionary Conservation Drosophila ctrip Intestinal Stem Cells |
| dc.title.none.fl_str_mv | Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12 |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Transforming growth factor β (TGFβ) pathway is a master regulator of cell proliferation, differentiation, and death. Deregulation of TGFβ signalling is well established in several human diseases including autoimmune disorders and cancer. Thus, understanding molecular pathways governing TGFβ signalling may help better understand the underlying causes of some of those conditions. Here, we show that a HECT domain E3 ubiquitin ligase TRIP12 controls TGFβ signalling in multiple models. Interestingly, <i>TRIP12</i> control of TGFβ signalling is completely independent of its E3 ubiquitin ligase activity. Instead, <i>TRIP12</i> recruits SMURF2 to SMAD4, which is most likely responsible for inhibitory monoubiquitination of SMAD4, since SMAD4 monoubiquitination and its interaction with SMURF2 were dramatically downregulated in <i>TRIP12</i><sup><em>-</em></sup><sup>/-</sup> cells. Additionally, genetic inhibition of TRIP12 in human and murine cells leads to robust activation of TGFβ signalling which was rescued by re-introducing wildtype TRIP12 or a catalytically inactive C1959A mutant. Importantly, TRIP12 control of TGFβ signalling is evolutionary conserved. Indeed, genetic inhibition of Drosophila TRIP12 orthologue, ctrip, in gut leads to a reduced number of intestinal stem cells which was compensated by the increase in differentiated enteroendocrine cells. These effects were completely normalised in Drosophila strain where ctrip was co-inhibited together with Drosophila<i> SMAD4 </i>orthologue, Medea. Similarly, in murine 3D intestinal organoids, CRISPR/Cas9 mediated genetic targeting of Trip12 enhances TGFβ mediated proliferation arrest and cell death. Finally, CRISPR/Cas9 mediated genetic targeting of <i>TRIP12</i> in MDA-MB-231 breast cancer cells enhances the TGFβ induced migratory capacity of these cells which was rescued to the wildtype level by re-introducing wildtype <i>TRIP12</i>. Our work establishes TRIP12 as an evolutionary conserved modulator of TGFβ signalling in health and disease.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Death & Disease<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41419-023-06215-y" target="_blank">https://dx.doi.org/10.1038/s41419-023-06215-y</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_2fbf9d95f3d48aa3ee40a70ce44a4d36 |
| identifier_str_mv | 10.1038/s41419-023-06215-y |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26798146 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12Kripa S Keyan (10644815)Safa Salim (9186786)Swetha Gowda (19459546)Doua Abdelrahman (17280667)Syeda Sakina Amir (19459549)Zeyaul Islam (5867387)Claire Vargas (19459552)Maria Teresa Bengoechea-Alonso (2936889)Amira Alwa (11438828)Subrat Dahal (19459555)Prasanna R. Kolatkar (124118)Sahar Da’as (15430086)Jerome Torrisani (19459558)Johan Ericsson (49714)Farhan Mohammad (256409)Omar M Khan (9260654)Biological sciencesGeneticsBiomedical and clinical sciencesClinical sciencesImmunologyOncology and carcinogenesisCell ProliferationCell DifferentiationCell DeathGenetic InhibitionEvolutionary ConservationDrosophila ctripIntestinal Stem Cells<p dir="ltr">Transforming growth factor β (TGFβ) pathway is a master regulator of cell proliferation, differentiation, and death. Deregulation of TGFβ signalling is well established in several human diseases including autoimmune disorders and cancer. Thus, understanding molecular pathways governing TGFβ signalling may help better understand the underlying causes of some of those conditions. Here, we show that a HECT domain E3 ubiquitin ligase TRIP12 controls TGFβ signalling in multiple models. Interestingly, <i>TRIP12</i> control of TGFβ signalling is completely independent of its E3 ubiquitin ligase activity. Instead, <i>TRIP12</i> recruits SMURF2 to SMAD4, which is most likely responsible for inhibitory monoubiquitination of SMAD4, since SMAD4 monoubiquitination and its interaction with SMURF2 were dramatically downregulated in <i>TRIP12</i><sup><em>-</em></sup><sup>/-</sup> cells. Additionally, genetic inhibition of TRIP12 in human and murine cells leads to robust activation of TGFβ signalling which was rescued by re-introducing wildtype TRIP12 or a catalytically inactive C1959A mutant. Importantly, TRIP12 control of TGFβ signalling is evolutionary conserved. Indeed, genetic inhibition of Drosophila TRIP12 orthologue, ctrip, in gut leads to a reduced number of intestinal stem cells which was compensated by the increase in differentiated enteroendocrine cells. These effects were completely normalised in Drosophila strain where ctrip was co-inhibited together with Drosophila<i> SMAD4 </i>orthologue, Medea. Similarly, in murine 3D intestinal organoids, CRISPR/Cas9 mediated genetic targeting of Trip12 enhances TGFβ mediated proliferation arrest and cell death. Finally, CRISPR/Cas9 mediated genetic targeting of <i>TRIP12</i> in MDA-MB-231 breast cancer cells enhances the TGFβ induced migratory capacity of these cells which was rescued to the wildtype level by re-introducing wildtype <i>TRIP12</i>. Our work establishes TRIP12 as an evolutionary conserved modulator of TGFβ signalling in health and disease.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Death & Disease<br>License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1038/s41419-023-06215-y" target="_blank">https://dx.doi.org/10.1038/s41419-023-06215-y</a></p>2023-10-20T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41419-023-06215-yhttps://figshare.com/articles/journal_contribution/Control_of_TGF_signalling_by_ubiquitination_independent_function_of_E3_ubiquitin_ligase_TRIP12/26798146CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/267981462023-10-20T09:00:00Z |
| spellingShingle | Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12 Kripa S Keyan (10644815) Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Immunology Oncology and carcinogenesis Cell Proliferation Cell Differentiation Cell Death Genetic Inhibition Evolutionary Conservation Drosophila ctrip Intestinal Stem Cells |
| status_str | publishedVersion |
| title | Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12 |
| title_full | Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12 |
| title_fullStr | Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12 |
| title_full_unstemmed | Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12 |
| title_short | Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12 |
| title_sort | Control of TGFβ signalling by ubiquitination independent function of E3 ubiquitin ligase TRIP12 |
| topic | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Immunology Oncology and carcinogenesis Cell Proliferation Cell Differentiation Cell Death Genetic Inhibition Evolutionary Conservation Drosophila ctrip Intestinal Stem Cells |