Shifting IRES Versus Cap-Initiated Translation During Homeostatic Stem Cell Differentiation and Stress

    May 2026 in “ Science Advances ”
    Michael Mazzola, Ting Zhao, Anna Kiem, Trine A. Kristiansen, Karin Gustafsson, Lai Ping Wong, Emily Scott-Solomon, Marissa 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
    TLDR Caloric stress and differentiation increase IRES translation, affecting stem cell function and potential therapies.
    The study explores the shift between internal ribosome entry site (IRES) and cap-dependent translation during stem cell differentiation and stress, using an IRES/Cap reporter mouse model. It reveals that caloric stress increases IRES/Cap translation across tissues, and this increase also occurs during normal differentiation of hematopoietic and hair follicle cells. Low IRES utilization is linked to higher multipotent capability, suggesting that cap-dependent translation is associated with greater stemness. The RNA processing protein PTBP1 regulates this translation preference, indicating that modulation of translation initiation is crucial for cell differentiation. The findings underscore the role of IRES-mediated translation in tissue differentiation and regeneration, with potential implications for understanding stem cell function and therapeutic strategies for conditions like hair loss.
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