PDF(Pubmed)
Abstract：
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 Npc2 family genes remain unexplored. Here, we focus on the intestinal function of Npc2c in the adult. We find that Npc2c 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 Npc2c-silenced midguts is accompanied by reduced expression of Cyclin genes, and genes encoding ISC regulators, such as Delta, unpaired1 and Socs36E. ISC-specific Npc2c silencing induces Attacin-A expression, a phenotype reminiscent of Gram-negative bacteria overabundance. Metagenomic analysis of Npc2c-depleted midguts indicates intestinal dysbiosis, whereby decreased commensal complexity is accompanied by increased gamma-proteobacteria. ISC-specific Npc2c silencing also results in increased cholesterol aggregation. Interestingly, administration of the non-steroidal ecdysone receptor agonist, RH5849, rescues mitosis of Npc2c-silenced midguts and increases expression of the ecdysone response gene Broad, underscoring the role of Npc2c and sterols in ecdysone signaling. Assessment of additional Npc2 family members indicates potential redundant roles with Npc2c in ISC control and response to ecdysone signaling. Our results highlight a previously unidentified essential role of Npc2c in ISC mitosis, as well as an important role in ecdysone signaling and microbiome composition in the Drosophila midgut.
摘要：
胆固醇是所有细胞发挥作用所必需的。细胞内胆固醇转运蛋白Npc1和Npc2控制固醇的运输，它们的功能障碍导致Neimann-PickC型疾病，一种影响神经系统和肠道的罕见疾病。与编码单个Npc1和Npc2转运蛋白的人类不同，苍蝇包括两个Npc1（Npc1a-1b）和八个Npc2（Npc2a-2h）成员，大多数Npc2家族基因仍未被研究。这里,我们关注Npc2c在成人中的肠道功能。我们发现Npc2c对肠干细胞（ISC）有丝分裂是必需的，维护ISC谱系，病原体感染后的生存，以及肿瘤的生长。Npc2c沉默的中肠的有丝分裂受损伴随着Cyclin基因的表达降低，和编码ISC调节因子的基因，比如Delta,unpaired1和Sock36E。ISC特异性Npc2c沉默诱导Attacin-A表达，一种让人联想到革兰氏阴性细菌过多的表型。Npc2c耗尽的中肠的宏基因组分析表明肠道生态失调，由此降低的共生复杂性伴随着增加的γ-变形杆菌。ISC特异性Npc2c沉默也导致胆固醇聚集增加。有趣的是,非甾体蜕皮激素受体激动剂的给药，RH5849，挽救Npc2c沉默的中肠的有丝分裂，并增加蜕皮激素反应基因Broad的表达，强调Npc2c和固醇在蜕皮激素信号传导中的作用。对其他Npc2家族成员的评估表明Npc2c在ISC控制和对蜕皮激素信号传导的反应中的潜在冗余作用。我们的结果强调了Npc2c在ISC有丝分裂中的一个先前尚未确定的重要作用，以及在果蝇中肠蜕皮激素信号传导和微生物组组成中的重要作用。
