The R2TP chaperone assembles cellular machineries in intestinal CBC stem cells and progenitors

Chloé Maurizy; Claire Abéza; Bénédicte Lemmers; Monica Gabola; Ciro Longobardi; Valérie Pinet; Marina Ferrand; Conception Paul; Julie Bremond; Francina Langa Vives; François Gerbe; Philippe Jay; Céline Verheggen; Nicola Tinari; Dominique Helmlinger; Rossano Lattanzio; Édouard Bertrand; Michael Hahne; Bérengère Pradet‐Balade

doi:10.1038/s41467-021-24792-4

Developmental BiologyNature CommunicationsAug 10, 2021

Peer-reviewed journal article

The R2TP chaperone assembles cellular machineries in intestinal CBC stem cells and progenitors

Chloé Maurizy iD, Claire Abéza iD, Bénédicte Lemmers iD, Monica Gabola iD, Ciro Longobardi iD, Valérie Pinet iD, Marina Ferrand iD, Conception Paul, Julie Bremond, Francina Langa Vives iD, François Gerbe iD, Philippe Jay iD, Céline Verheggen iD, Nicola Tinari iD, Dominique Helmlinger iD, Rossano Lattanzio iD, Édouard Bertrand iD, Michael Hahne iD, Bérengère Pradet‐Balade iD

Abstract

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 were decreased, with strong effects on mTOR, ATM and ATR. Rpap3-deficient CBC stem cells and progenitors also failed to import RNA polymerase II in the nucleus. This correlated with p53 activation, cell cycle arrest and apoptosis. Interestingly, post-mitotic, differentiated cells did not display any of those alterations, indicating that R2TP clients are built in actively proliferating cells. Analyses of tissues from colorectal cancer patients revealed that high RPAP3 levels correlate with bad cancer prognosis. Thus, in the intestine, the R2TP chaperone functions in physiologic and pathologic proliferation.

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