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

Daniel, S.; Ghanem, R.; Makhzumy, M.; Bitman-Lotan, E.; Soffers, J.; Henriksen, J. c.; Sarusi-Portuguez, A.; Rissland, O. S.; Mohan, R. D.; Shiber, A.; Orian, A. M.

doi:10.64898/2026.03.06.709266

bioRxiv · 10.64898/2026.03.06.709266

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

Daniel, S.·Ghanem, R.·Makhzumy, M.·Bitman-Lotan, E.·Soffers, J.·Henriksen, J. c.·Sarusi-Portuguez, A.·Rissland, O. S.·Mohan, R. D.·Shiber, A.·Orian, A. M.

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Abstract

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.

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Daniel, S., Ghanem, R., Makhzumy, M., Bitman-Lotan, E., Soffers, J., Henriksen, J. c., Sarusi-Portuguez, A., Rissland, O. S., Mohan, R. D., Shiber, A., Orian, A. M.. 2026-03-08. A Ubiquitin network safeguards cell identity by continuously degrading stem-cell related translational machinery. https://doi.org/10.64898/2026.03.06.709266

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