A Ubiquitin network safeguards cell identity by continuously degrading stem-cell related translational machinery

How cell identity is maintained is a fundamental question, and loss of cell identity is a hallmark of aging that is associated with multiple age-related diseases. In the adult Drosophila midgut, we identified a post-transcriptional regulatory layer that supervises enterocyte (EC) identity and fails upon aging. Combining single-cell RNA-seq with lineage tracing in aging ECs and classical genetics we found that aging ECs express genes that unlock the differentiated state. Upon aging, the protein Rogue (CG13928), a translational repressor, orchestrates reactivation of a stem-cell-related translational repression machinery involving p-body-associated RNA-binding proteins that cancels the differentiated state. In young ECs, this machinery is continuously suppressed by the deubiquitinase Non-stop (dUSP22) and the ubiquitin E2 dUbcH8/Kdo and the E3 enzyme CTLH, together suppress the stem-cell related RNA binding proteins safeguarding EC identity. Upon aging, the levels of dUSP22 decline, dUbcH8/Kdo and the E3 CTLH complex are cleared via Rogue, and the stem cell-related p-bodies are reactivated, self-destroying EC identity.