miR-137 regulates PTP61F, affecting insulin signaling, metabolic homeostasis, and starvation resistance in Drosophila

• 成果类型: Article
• 署名作者: Saedi, Hana; Waro, Girma; Giacchetta, Lea; Tsunoda, Susan
• 署名单位: Colorado State University System; Colorado State University Fort Collins
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15431
• DOI: 10.1073/pnas.2319475121
• 发表日期: 2024-01-30
• 关键词: suppresses tumor-growth; k-atp channels; life-span; glucose-homeostasis; stress resistance; receptor homolog; melanoma-cells; microrna-137; schizophrenia; gene

摘要

miR-137is a highly conserved brain- enriched microRNA (miRNA) that has been associated with neuronal function and proliferation. Here, we show that Drosophila miR-137 null mutants display increased body weight with enhanced triglyceride content and decreased locomotor activity. In addition, when challenged by nutrient deprivation, miR-137 mutants exhibit reduced motivation to feed and prolonged survival. We show through genetic epistasis and rescue experiments that this starvation resistance is due to a disruption in insulin signaling. Our studies further show that miR-137 null mutants exhibit a drastic reduction in levels of the phosphorylated/activated insulin receptor, InR (InR- P). We investigated if this is due to the predicted miR-137 target, Protein Tyrosine Phosphatase 61F (PTP61F), ortholog of mammalian TC-PTP/PTP1B, which are known to dephosphorylate InR-P. Indeed, levels of an endogenously tagged GFP- PTP61F are significantly elevated in miR- 137null mutants, and we show that overexpression ofPTP61F alone is sufficient to mimic many of the metabolic phenotypes of miR- 137mutants. Finally, we knocked - down elevated levels of PTP61F in the miR-137 null mutant background and show that this rescues levels of InR-P, restores normal body weight and triglyceride content, starvation sensitivity, as well as attenuates locomotor and starvation- induced feeding defects. Our study supports a model in which miR-137 is critical for dampening levels of PTP61F, thereby maintaining normal insulin signaling and energy homeostasis.