AutophagyJul 30, 2026

Turning off V-ATPase triggers cell recycling and abnormal Notch signaling to help intestinal stem cells develop in adult fruit flies

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Aug 4, 2026

Abstract

A large-scale RNA interference screen identifies Vha68-2 as crucial for the proliferation and differentiation of adult Drosophila intestinal stem cells.

Inactivation of Vha68-2 leads to the buildup of plasma membrane-derived structures in autophagosomes and lysosomes.
Defective ISCs lacking Vha68-2 exhibit ectopic activation of the Notch signaling pathway, causing direct differentiation.
Vha68-2 is essential for the internalization and degradation of Notch receptors, which helps regulate stem cell fate.
Accumulation of a truncated Notch product occurs in autolysosomes when Vha68-2 is deficient, indicating disrupted Notch processing.
The roles of Vha68-2 in autophagy and stem cell maintenance appear to be conserved across evolution.

Simplified

The self-renewal and differentiation of stem cells are tightly controlled to maintain tissue homeostasis. Failure in stem cell maintenance results in stem cell depletion and precocious aging. However, how stem cells are maintained still remains not fully understood. Here, through a large-scale RNAi screen for maintenance and proliferation of adult Drosophila intestinal stem cells (ISCs), we identify several subunits of V-ATPase including Vha68-2/ATP6V1A, required for ISC proliferation, differentiation and tissue regeneration. Inactivation of Vha68-2 results in accumulation of plasma membrane (PM)-derived structures in autophagosomes and lysosomes through Atg16 and Rab5. Furthermore, Vha68-2-defective ISCs undergo direct differentiation due to ectopic Notch activation. Mechanistically, Vha68-2 facilitates Notch receptor internalization and subsequent degradation in autolysosomes to quench ectopic Notch activation, thereby maintaining ISC fate. Truncated Notch product devoid of its extracellular domain is accumulated in autolysosomes upon Vha68-2 deficiency. The Notch products accumulated in autolysosomes still require further cleavage to drive ISC differentiation. The functions of Vha68-2 in macroautophagy/autophagy and ISC maintenance are evolutionarily conserved. Our results provide new insights into the underlying mechanism of how autophagy is involved in stem cell maintenance under physiological conditions.

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Turning off V-ATPase triggers cell recycling and abnormal Notch signaling to help intestinal stem cells develop in adult fruit flies

Abstract

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