The HSP90/R2TP Quaternary Chaperone Scaffolds Assembly of the TSC Complex
The R2TP chaperone is composed of the RUVBL1/RUVBL2 AAA+ ATPases and two adapter proteins, RPAP3 and PIH1D1. Together with HSP90, it functions in the assembly of macromolecular complexes that are often involved in cell proliferation. Here, proteomic experiments using the isolated PIH domain reveals additional R2TP partners, including the Tuberous Sclerosis Complex (TSC) and many transcriptional complexes. The TSC is a key regulator of mTORC1 and is composed of TSC1, TSC2 and TBC1D7. We show a direct interaction of TSC1 with the PIH phospho-binding domain of PIH1D1, which is, surprisingly, phosphorylation independent. Via the use of mutants and KO cell lines, we observe that TSC2 makes independent interactions with HSP90 and the TPR domains of RPAP3. Moreover, inactivation of PIH1D1 or the RUVBL1/2 ATPase activity inhibits the association of TSC1 with TSC2. Taken together, these data suggest a model in which the R2TP recruits TSC1 via PIH1D1 and TSC2 via RPAP3 and HSP90, and use the chaperone-like activities of RUVBL1/2 to stimulate their assembly.
Authors
- Édouard Bertrand (ORCID: https://orcid.org/0000-0002-9642-7994)
- Pedro M. F. Sousa (ORCID: https://orcid.org/0000-0002-6672-3610)
- Justine Schneider (ORCID: https://orcid.org/0000-0002-5863-7747)
- Philipp Busse (ORCID: https://orcid.org/0000-0001-8728-017X)
- Claire Abéza (ORCID: https://orcid.org/0000-0003-0072-8248)
- Xavier Manival (ORCID: https://orcid.org/0000-0002-7717-7096)
- Christine Schaeffer‐Reiss (ORCID: https://orcid.org/0000-0003-0672-1979)
- Ana C. F. Paiva (ORCID: https://orcid.org/0000-0002-3637-7702)
- Bruno Charpentier (ORCID: https://orcid.org/0000-0003-2955-2987)
- Marie-Cécile Robert (ORCID: https://orcid.org/0000-0003-1603-4187)
- Tiago M. Bandeiras (ORCID: https://orcid.org/0000-0001-6089-6089)
- Sarah Cianférani (ORCID: https://orcid.org/0000-0003-4013-4129)
- Céline Verheggen (ORCID: https://orcid.org/0000-0003-2459-9700)
- Franck Vandermoere (ORCID: https://orcid.org/0000-0001-5724-7037)
- Marie-Eve Chagot
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Ingénierie Moléculaire et Physiopathologie Articulaire (FR)
- Université de Lorraine (FR)
Publication Details
- Journal
- Journal of Molecular Biology
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1016/j.jmb.2024.168840
- Citations
- 5
- Primary Topic
- Heat shock proteins research
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- Université de Lorraine
- Agência Regional para o Desenvolvimento da Investigação, Tecnologia e Inovação
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Ministério da Ciência, Tecnologia e Ensino Superior
- Institut National Du Cancer
- Université de Montpellier
- Fundação para a Ciência e a Tecnologia