Uncoupling of ribosome biogenesis and Tor activation by TRIM-NHL proteins promotes terminal differentiation

Proper stem cell differentiation relies on a balance between cellular growth and terminal differentiation, but the mechanisms coordinating these processes remain elusive. Recent studies indicate that ribosome biogenesis (RiBi) and protein synthesis, two of the most energy-consuming cellular processes supporting growth, are tightly regulated and yet can be uncoupled during stem cell fate transitions. Here, using the Drosophila adult female germline stem cell (GSC) and larval neuroblast (NB) systems, we show that Mei-P26 and Brat, two Drosophila TRIM-NHL paralogues of the mammalian TRIM32 protein family, are responsible for uncoupling RiBi and protein synthesis during GSC and NB differentiation, respectively. This is achieved by TRIM-NHL-mediated activation of the Target of rapamycin (Tor) kinase and concomitant repression of RiBi specifically during stem cell differentiation. In consequence, the anabolic reprogramming established by TRIM-NHL activity creates the conditions for terminal differentiation. In agreement with this, depletion of mei-P26 or brat, which results in excessive cellular growth and defective terminal differentiation, can be counterbalanced by ectopic activation of Tor together with suppression of RiBi, allowing completion of differentiation. Our work indicates that TRIM-NHL proteins uncouple RiBi and translation activities to coordinate growth and differentiation, and proposes that the control of cellular resources provides a meter for terminal differentiation.