| Summary: | Cholesterol is necessary for all cells to function. The intracellular cholesterol transporters Npc1 and Npc2 control sterol trafficking and their malfunction leads to Neimann–Pick Type C disease, a rare disorder affecting the nervous system and the intestine. Unlike humans that encode single Npc1 and Npc2 transporters, flies encompass two Npc1 (Npc1a-1b) and eight Npc2 (Npc2a-2h) members, and most of the <i>Npc2</i> family genes remain unexplored. Here, we focus on the intestinal function of <i>Npc2c</i> in the adult. We find that <i>Npc2c</i> is necessary for intestinal stem cell (ISC) mitosis, maintenance of the ISC lineage, survival upon pathogenic infection, as well as tumor growth. Impaired mitosis of <i>Npc2c</i>-silenced midguts is accompanied by reduced expression of <i>Cyclin</i> genes, and genes encoding ISC regulators, such as <i>Delta</i>, <i>unpaired1</i> and <i>Socs36E</i>. ISC-specific <i>Npc2c</i> silencing induces <i>Attacin</i>-<i>A</i> expression, a phenotype reminiscent of Gram-negative bacteria overabundance. Metagenomic analysis of <i>Npc2c</i>-depleted midguts indicates intestinal dysbiosis, whereby decreased commensal complexity is accompanied by increased gamma-proteobacteria. ISC-specific <i>Npc2c</i> silencing also results in increased cholesterol aggregation. Interestingly, administration of the non-steroidal ecdysone receptor agonist, RH5849, rescues mitosis of <i>Npc2c</i>-silenced midguts and increases expression of the ecdysone response gene <i>Broad</i>, underscoring the role of <i>Npc2c</i> and sterols in ecdysone signaling. Assessment of additional <i>Npc2</i> family members indicates potential redundant roles with <i>Npc2c</i> in ISC control and response to ecdysone signaling. Our results highlight a previously unidentified essential role of <i>Npc2c</i> in ISC mitosis, as well as an important role in ecdysone signaling and microbiome composition in the <i>Drosophila</i> midgut.
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