ABSTRACTThere is increasing evidence associating the activity of caspases with the regulation of basic cellular functions beyond apoptosis. Accordingly, the dysregulation of these novel non-apoptotic functions often sits at the origin of neurological disorders, metabolic defects, autoimmunity, and cancer. However, the molecular interplay between caspases and the signalling networks active in non-apoptotic cellular scenarios remains largely unknown. Our experiments show that non-apoptotic caspase activation is critical to modulate Hedgehog-signalling and autophagy in ovarian somatic cells from both Drosophila and humans under moderate stress. We also demonstrate that these novel caspase functions are key to sustain stem cell proliferation and differentiation without inducing apoptosis. Finally, we molecularly link these caspase-dependent effects to the fine-tuning of the Hedgehog-receptor, Patched. Together, these findings confer a pro-survival role to the caspases, as opposed to the widely held apoptotic function assigned to these enzymes for many years.
Current evidence has associated caspase activation with the regulation of basic cellular functions without causing apoptosis. Malfunction of non‐apoptotic caspase activities may contribute to specific neurological disorders, metabolic diseases, autoimmune conditions and cancers. However, our understanding of non‐apoptotic caspase functions remains limited. Here, we show that non‐apoptotic caspase activation prevents the intracellular accumulation of the Patched receptor in autophagosomes and the subsequent Patched‐dependent induction of autophagy in Drosophila follicular stem cells. These events ultimately sustain Hedgehog signalling and the physiological properties of ovarian somatic stem cells and their progeny under moderate thermal stress. Importantly, our key findings are partially conserved in ovarian somatic cells of human origin. These observations attribute to caspases a pro‐survival role under certain cellular conditions.
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