Disruption of the lipolysis pathway results in stem cell death through a sterile immunity-like pathway in adult Drosophila

• Published in: Cell reports (Cambridge) 2022-06, Vol.39 (12), p.110958-110958, Article 110958
• Main Authors: Aggarwal, Poonam, Liu, Zilun, Cheng, Guang Qian, Singh, Shree Ram, Shi, Chunmei, Chen, Ying, Sun, Ling V., Hou, Steven X.
• Format: Article
• Language: English
• Subjects: aging cascade; Arf1; CSC; DAMPs; immunogenic cell death; inflammasome; lipid metabolism; lipolysis; metabolic stress; stem cell
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110958

We previously showed that the Arf1-mediated lipolysis pathway sustains stem cells and cancer stem cells (CSCs); its ablation resulted in necrosis of stem cells and CSCs, which further triggers a systemic antitumor immune response. Here we show that knocking down Arf1 in intestinal stem cells (ISCs) causes metabolic stress, which promotes the expression and translocation of ISC-produced damage-associated molecular patterns (DAMPs; Pretaporter [Prtp] and calreticulin [Calr]). DAMPs regulate macroglobulin complement-related (Mcr) expression and secretion. The secreted Mcr influences the expression and localization of enterocyte (EC)-produced Draper (Drpr) and LRP1 receptors (pattern recognition receptors [PRRs]) to activate autophagy in ECs for ATP production. The secreted ATP possibly feeds back to kill ISCs by activating inflammasome-like pyroptosis. We identify an evolutionarily conserved pathway that sustains stem cells and CSCs, and its ablation results in an immunogenic cascade that promotes death of stem cells and CSCs as well as antitumor immunity. [Display omitted] •Knocking down Arf1 results in stem cell death through a sterile immunity-like pathway•Knocking down Arf1 in intestinal stem cells induces expression of Prtp and Calr•Prtp and Calr induce expression of Drpr and LRP1 in ECs via Mcr to produce ATP•ATP kills ISCs by activating inflammasome-like pyroptosis Aggarwal et al. show that disruption of Arf1-mediated lipolysis results in stem cell death through a sterile immunity-like pathway in adult Drosophila. They identify an evolutionarily conserved pathway that specifically sustains stem cells and cancer stem cells (CSCs), and its ablation results in an immunogenic cascade that promotes death of stem cells and CSCs as well as antitumor immunity.