The HSP90/R2TP assembly chaperone promotes cell proliferation in the intestinal epithelium

Autor: Marina Ferrand, Edouard Bertrand, Bénédicte Lemmers, Claire Abeza, Francina Langa, Conception Paul, Céline Verheggen, Valérie Pinet, Dominique Helmlinger, Bérengère Pradet-Balade, Rossano Lattanzio, Ciro Longobardi, Michael Hahne, Philippe Jay, François Gerbe, Monica Gabola, Julie Bremond, Chloé Maurizy, Nicola Tinari
Přispěvatelé: Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM), Institut Pasteur [Paris] (IP), Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de génétique humaine (IGH), Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Centre de recherche en Biologie cellulaire de Montpellier (CRBM), The work was supported by La Ligue Nationale Contre le Cancer (équipes labelisées to E.B., P.J.) and the INCa grants PLBIO 2016-161 to D.H., E.B., M.H., B.P.B., and PLBIO 2018-158 to P.J. C.M. and C.A. had fellowships from la Ligue Nationale Contre le Cancer., Guerineau, Nathalie C., Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut Pasteur [Paris], Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en Biologie Cellulaire (CRBM), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
Rok vydání: 2020
Předmět:
Cellular differentiation
General Physics and Astronomy
MESH: Mice
Knockout
0302 clinical medicine
Chaperones
MESH: Microscopy
Confocal
MESH: Animals
Intestinal Mucosa
Tissue homeostasis
Cells
Cultured
Mice
Knockout
0303 health sciences
Multidisciplinary
Microscopy
Confocal
biology
Chemistry
Stem Cells
Intestinal stem cells
Intestinal epithelium
3. Good health
Cell biology
MESH: Epithelial Cells
030220 oncology & carcinogenesis
MESH: Intestinal Mucosa
Stem cell
MESH: Molecular Chaperones
MESH: Cells
Cultured
Protein Binding
MESH: Mice
Transgenic
Science
Mice
Transgenic
MESH: Stem Cells
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
MESH: Mice
Inbred C57BL
MESH: Cell Proliferation
MESH: HSP90 Heat-Shock Proteins
[SDV.BBM] Life Sciences [q-bio]/Biochemistry
Molecular Biology
MESH: Protein Binding
Animals
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry
Molecular Biology
HSP90 Heat-Shock Proteins
Progenitor cell
PI3K/AKT/mTOR pathway
030304 developmental biology
Cell Proliferation
MESH: Humans
Cell growth
Epithelial Cells
General Chemistry
Mice
Inbred C57BL
Chaperone (protein)
biology.protein
Molecular Chaperones
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-19 (2021)
Nature Communications
Nature Communications, 2021, 12 (1), pp.4810. ⟨10.1038/s41467-021-24792-4⟩
Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.4810. ⟨10.1038/s41467-021-24792-4⟩
ISSN: 2041-1723
Popis: The R2TP chaperone cooperates with HSP90 to integrate newly synthesized proteins into multi-subunit complexes, yet its role in tissue homeostasis is unknown. Here, we generated conditional, inducible knock-out mice for Rpap3 to inactivate this core component of R2TP in the intestinal epithelium. In adult mice, Rpap3 invalidation caused destruction of the small intestinal epithelium and death within 10 days. Levels of R2TP substrates decreased, with strong effects on mTOR, ATM and ATR. Proliferative stem cells and progenitors deficient for Rpap3 failed to import RNA polymerase II into the nucleus and they induced p53, cell cycle arrest and apoptosis. Post-mitotic, differentiated cells did not display these alterations, suggesting that R2TP clients are preferentially built in actively proliferating cells. In addition, high RPAP3 levels in colorectal tumors from patients correlate with bad prognosis. Here, we show that, in the intestine, the R2TP chaperone plays essential roles in normal and tumoral proliferation.
RPAP3 is a subunit of the R2TP complex, a co-chaperone of HSP90, with substrate proteins involved in transcription, ribosome biogenesis, DNA repair and cell growth. Here the authors report that deletion of Rpap3 abrogates cell proliferation and homeostasis in mouse intestine, partly through destabilization of PI3K-like kinases, while elevated RPAP3 levels in colorectal tumors are associated with poor prognosis.
Databáze: OpenAIRE
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