Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12
<div><p>The tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA li...
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2021
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| _version_ | 1864513515324178432 |
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| author | Omar M. Khan (17807774) |
| author2 | Jorge Almagro (8692275) Jessica K. Nelson (3775789) Stuart Horswell (594411) Vesela Encheva (4917094) Kripa S. Keyan (17807771) Bruce E. Clurman (18595726) Ambrosius P. Snijders (3192861) Axel Behrens (47682) |
| author2_role | author author author author author author author author |
| author_facet | Omar M. Khan (17807774) Jorge Almagro (8692275) Jessica K. Nelson (3775789) Stuart Horswell (594411) Vesela Encheva (4917094) Kripa S. Keyan (17807771) Bruce E. Clurman (18595726) Ambrosius P. Snijders (3192861) Axel Behrens (47682) |
| author_role | author |
| dc.creator.none.fl_str_mv | Omar M. Khan (17807774) Jorge Almagro (8692275) Jessica K. Nelson (3775789) Stuart Horswell (594411) Vesela Encheva (4917094) Kripa S. Keyan (17807771) Bruce E. Clurman (18595726) Ambrosius P. Snijders (3192861) Axel Behrens (47682) |
| dc.date.none.fl_str_mv | 2021-04-06T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41467-021-22319-5 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Proteasomal_degradation_of_the_tumour_suppressor_FBW7_requires_branched_ubiquitylation_by_TRIP12/25877989 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Oncology and carcinogenesis Tumour suppressor FBW7 E3 ubiquitin ligase SKP1-CUL1-F-box (SCF) complex Oncoproteins Proteasomal degradation Cancer |
| dc.title.none.fl_str_mv | Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12 |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <div><p>The tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCFFBW7-mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCFFBW7 substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Nature Communications<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/s41467-021-22319-5" target="_blank">https://dx.doi.org/10.1038/s41467-021-22319-5</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_8b4581c680d382ebbe54781300429aa8 |
| identifier_str_mv | 10.1038/s41467-021-22319-5 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25877989 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12Omar M. Khan (17807774)Jorge Almagro (8692275)Jessica K. Nelson (3775789)Stuart Horswell (594411)Vesela Encheva (4917094)Kripa S. Keyan (17807771)Bruce E. Clurman (18595726)Ambrosius P. Snijders (3192861)Axel Behrens (47682)Biomedical and clinical sciencesOncology and carcinogenesisTumour suppressorFBW7E3 ubiquitin ligaseSKP1-CUL1-F-box (SCF) complexOncoproteinsProteasomal degradationCancer<div><p>The tumour suppressor FBW7 is a substrate adaptor for the E3 ubiquitin ligase complex SKP1-CUL1-F-box (SCF), that targets several oncoproteins for proteasomal degradation. FBW7 is widely mutated and FBW7 protein levels are commonly downregulated in cancer. Here, using an shRNA library screen, we identify the HECT-domain E3 ubiquitin ligase TRIP12 as a negative regulator of FBW7 stability. We find that SCFFBW7-mediated ubiquitylation of FBW7 occurs preferentially on K404 and K412, but is not sufficient for its proteasomal degradation, and in addition requires TRIP12-mediated branched K11-linked ubiquitylation. TRIP12 inactivation causes FBW7 protein accumulation and increased proteasomal degradation of the SCFFBW7 substrate Myeloid Leukemia 1 (MCL1), and sensitizes cancer cells to anti-tubulin chemotherapy. Concomitant FBW7 inactivation rescues the effects of TRIP12 deficiency, confirming FBW7 as an essential mediator of TRIP12 function. This work reveals an unexpected complexity of FBW7 ubiquitylation, and highlights branched ubiquitylation as an important signalling mechanism regulating protein stability.</p><p> </p></div><h2>Other Information</h2> <p> Published in: Nature Communications<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/s41467-021-22319-5" target="_blank">https://dx.doi.org/10.1038/s41467-021-22319-5</a></p>2021-04-06T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41467-021-22319-5https://figshare.com/articles/journal_contribution/Proteasomal_degradation_of_the_tumour_suppressor_FBW7_requires_branched_ubiquitylation_by_TRIP12/25877989CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/258779892021-04-06T03:00:00Z |
| spellingShingle | Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12 Omar M. Khan (17807774) Biomedical and clinical sciences Oncology and carcinogenesis Tumour suppressor FBW7 E3 ubiquitin ligase SKP1-CUL1-F-box (SCF) complex Oncoproteins Proteasomal degradation Cancer |
| status_str | publishedVersion |
| title | Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12 |
| title_full | Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12 |
| title_fullStr | Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12 |
| title_full_unstemmed | Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12 |
| title_short | Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12 |
| title_sort | Proteasomal degradation of the tumour suppressor FBW7 requires branched ubiquitylation by TRIP12 |
| topic | Biomedical and clinical sciences Oncology and carcinogenesis Tumour suppressor FBW7 E3 ubiquitin ligase SKP1-CUL1-F-box (SCF) complex Oncoproteins Proteasomal degradation Cancer |