Shifting IRES versus Cap-initiated translation during homeostatic stem cell differentiation and stress
- Michael C. Mazzola
- Ting Zhao
- Anna Kiem
- Trine A. Kristiansen
- Karin Gustafsson
- Lai Ping Wong
- Emily Scott-Solomon
- Marissa D. Fahlberg
- Christina Mayerhofer
- Ernst Mayerhofer
- Sarah Forward
- Emane Rose Assita
- Giulia Schiroli
- Maris Handley
- Youmna Kfoury
- Tsuyoshi Fukushima
- Dan Li
- Samuel Keyes
- Azeem Sharda
- Jelena Milosevic
- Hiroki Kato
- Pavel Ivanov
- David B. Sykes
- Sheldon J. J. Kwok
- Ruslan I. Sadreyev
- Vijay G. Sankaran
- Ya-Chieh Hsu
- David T. Scadden
2026-05-22
Cell stress can increase the use of methylated guanosine (m 7 G) cap–independent, internal ribosome entry site (IRES)–mediated translation initiation relative to cap-dependent translation (IRES/Cap). Reporters that quantify IRES/Cap have demonstrated differential activity across cultured cell types and stress conditions. By generating an IRES/Cap reporter mouse, we were able to systematically evaluate IRES/Cap across distinct tissues and cell types during physiological stresses and lineage commitment. Caloric stress invoked the expected boost in IRES/Cap translation regardless of differentiation state, but unexpectedly, IRES/Cap progressively increased during hematopoietic and epithelial (hair follicle) differentiation under normal, homeostatic conditions. This was independent of total protein output or cell cycle. Even within cells of a given differentiation state, cells with lower relative IRES utilization had markedly higher multipotent capability in vivo. The RNA processing protein PTBP1 is a mediator of this translation initiation preference. Therefore, low IRES/Cap is a signature of high stemness and suggests that modulation of translation initiation participates in cell differentiation state.