The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity.
There are three prolyl hydroxylases (PHD1, 2 and 3) that regulate the hypoxia-inducible factors (HIFs), the master transcriptional regulators that respond to changes in intracellular O(2) tension. In high O(2) tension (normoxia) the PHDs hydroxylate two conserved proline residues on HIF-1α, which le...
| Main Authors: | , , , , , , , , , , , , , |
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| Formato: | Journal article |
| Idioma: | English |
| Publicado: |
2012
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| _version_ | 1826277381474615296 |
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| author | Foxler, D Bridge, K James, V Webb, T Mee, M Wong, S Feng, Y Constantin-Teodosiu, D Petursdottir, T Bjornsson, J Ingvarsson, S Ratcliffe, P Longmore, G Sharp, T |
| author_facet | Foxler, D Bridge, K James, V Webb, T Mee, M Wong, S Feng, Y Constantin-Teodosiu, D Petursdottir, T Bjornsson, J Ingvarsson, S Ratcliffe, P Longmore, G Sharp, T |
| author_sort | Foxler, D |
| collection | OXFORD |
| description | There are three prolyl hydroxylases (PHD1, 2 and 3) that regulate the hypoxia-inducible factors (HIFs), the master transcriptional regulators that respond to changes in intracellular O(2) tension. In high O(2) tension (normoxia) the PHDs hydroxylate two conserved proline residues on HIF-1α, which leads to binding of the von Hippel-Lindau (VHL) tumour suppressor, the recognition component of a ubiquitin-ligase complex, initiating HIF-1α ubiquitylation and degradation. However, it is not known whether PHDs and VHL act separately to exert their enzymatic activities on HIF-1α or as a multiprotein complex. Here we show that the tumour suppressor protein LIMD1 (LIM domain-containing protein) acts as a molecular scaffold, simultaneously binding the PHDs and VHL, thereby assembling a PHD-LIMD1-VHL protein complex and creating an enzymatic niche that enables efficient degradation of HIF-1α. Depletion of endogenous LIMD1 increases HIF-1α levels and transcriptional activity in both normoxia and hypoxia. Conversely, LIMD1 expression downregulates HIF-1 transcriptional activity in a manner depending on PHD and 26S proteasome activities. LIMD1 family member proteins Ajuba and WTIP also bind to VHL and PHDs 1 and 3, indicating that these LIM domain-containing proteins represent a previously unrecognized group of hypoxic regulators. |
| first_indexed | 2024-03-06T23:28:03Z |
| format | Journal article |
| id | oxford-uuid:6b13dc4c-b92c-4eec-90f6-3a5b0421cccc |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:28:03Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:6b13dc4c-b92c-4eec-90f6-3a5b0421cccc2022-03-26T19:01:25ZThe LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6b13dc4c-b92c-4eec-90f6-3a5b0421ccccEnglishSymplectic Elements at Oxford2012Foxler, DBridge, KJames, VWebb, TMee, MWong, SFeng, YConstantin-Teodosiu, DPetursdottir, TBjornsson, JIngvarsson, SRatcliffe, PLongmore, GSharp, TThere are three prolyl hydroxylases (PHD1, 2 and 3) that regulate the hypoxia-inducible factors (HIFs), the master transcriptional regulators that respond to changes in intracellular O(2) tension. In high O(2) tension (normoxia) the PHDs hydroxylate two conserved proline residues on HIF-1α, which leads to binding of the von Hippel-Lindau (VHL) tumour suppressor, the recognition component of a ubiquitin-ligase complex, initiating HIF-1α ubiquitylation and degradation. However, it is not known whether PHDs and VHL act separately to exert their enzymatic activities on HIF-1α or as a multiprotein complex. Here we show that the tumour suppressor protein LIMD1 (LIM domain-containing protein) acts as a molecular scaffold, simultaneously binding the PHDs and VHL, thereby assembling a PHD-LIMD1-VHL protein complex and creating an enzymatic niche that enables efficient degradation of HIF-1α. Depletion of endogenous LIMD1 increases HIF-1α levels and transcriptional activity in both normoxia and hypoxia. Conversely, LIMD1 expression downregulates HIF-1 transcriptional activity in a manner depending on PHD and 26S proteasome activities. LIMD1 family member proteins Ajuba and WTIP also bind to VHL and PHDs 1 and 3, indicating that these LIM domain-containing proteins represent a previously unrecognized group of hypoxic regulators. |
| spellingShingle | Foxler, D Bridge, K James, V Webb, T Mee, M Wong, S Feng, Y Constantin-Teodosiu, D Petursdottir, T Bjornsson, J Ingvarsson, S Ratcliffe, P Longmore, G Sharp, T The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. |
| title | The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. |
| title_full | The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. |
| title_fullStr | The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. |
| title_full_unstemmed | The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. |
| title_short | The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity. |
| title_sort | limd1 protein bridges an association between the prolyl hydroxylases and vhl to repress hif 1 activity |
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