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Olfaction regulates organismal proteostasis and longevity via microRNA-dependent signaling.

ABSTRACT: The maintenance of proteostasis is crucial for any organism to survive and reproduce in an ever-changing environment, but its efficiency declines with age1. Posttranscriptional regulators such as microRNAs control protein translation of target mRNAs with major consequences for development, physiology, and longevity2,3. Here we show that food odor stimulates organismal proteostasis and promotes longevity in Caenorhabditis elegans through mir-71-mediated inhibition of tir-1 mRNA stability in olfactory AWC neurons. Screening a collection of microRNAs that control aging3 we find that miRNA mir-71 regulates lifespan and promotes ubiquitin-dependent protein turnover, particularly in the intestine. We show that mir-71 directly inhibits the toll receptor domain protein TIR-1 in AWC olfactory neurons and that disruption of mir-71/tir-1 or loss of AWC olfactory neurons eliminates the influence of food source on proteostasis. mir-71-mediated regulation of TIR-1 controls chemotactic behavior and is regulated by odor. Thus, odor perception influences cell-type specific miRNA-target interaction to regulate organismal proteostasis and longevity. We anticipate that the proposed mechanism of food perception will stimulate further research on neuroendocrine brain-to-gut communication and may open the possibility for therapeutic interventions to improve proteostasis and organismal health via the sense of smell, with potential implication for obesity, diabetes and aging.

SUBMITTER: Finger F

PROVIDER: S-EPMC6751085 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Olfaction regulates organismal proteostasis and longevity via microRNA-dependent signaling.

Finger Fabian F Ottens Franziska F Springhorn Alexander A Drexel Tanja T Proksch Lucie L Metz Sophia S Cochella Luisa L Hoppe Thorsten T

Nature metabolism 20190218 3

The maintenance of proteostasis is crucial for any organism to survive and reproduce in an ever-changing environment, but its efficiency declines with age1. Posttranscriptional regulators such as microRNAs control protein translation of target mRNAs with major consequences for development, physiology, and longevity2,3. Here we show that food odor stimulates organismal proteostasis and promotes longevity in Caenorhabditis elegans through mir-71-mediated inhibit ...[more]

PMID: 31535080

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Project description:Stem cell pluripotency, angiogenesis and epithelial-mesenchymal transition (EMT) have been shown to be significantly upregulated in pancreatic ductal adenocarcinoma (PDAC) and many other aggressive cancers. The dysregulation of these processes is believed to play key roles in tumor initiation, progression, and metastasis, and is contributory to PDAC being the fourth leading cause of cancer-related deaths in the US. The tumor suppressor miRNA miR-145 downregulates critical pluripotency factors and oncogenes and results in repressed metastatic potential in PDAC. Additionally, the miR-200 family regulates several angiogenic factors which have been linked to metastasis in many solid tumors. We have previously demonstrated that downregulation of DCLK1 can upregulate critical miRNAs in both in vitro and in vivo cancer models and results in downregulation of c-MYC, KRAS, NOTCH1 and EMT-related transcription factors. A recent report has also shown that Dclk1 can distinguish between normal and tumor stem cells in Apc (min/+) mice and that ablation of Dclk1(+) cells resulted in regression of intestinal polyps without affecting homeostasis. Here we demonstrate that the knockdown of DCLK1 using poly(lactide-co-glycolide)-encapsulated-DCLK1-siRNA results in AsPC1 tumor growth arrest. Examination of xenograft tumors revealed, (a) increased miR-145 which results in decreased pluripotency maintenance factors OCT4, SOX2, NANOG, KLF4 as well as KRAS and RREB1; (b) increased let-7a which results in decreased pluripotency factor LIN28B; and (c) increased miR-200 which results in decreased VEGFR1, VEGFR2 and EMT-related transcription factors ZEB1, ZEB2, SNAIL and SLUG. Specificity of DCLK1 post-transcriptional regulation of the downstream targets of miR-145, miR-200 and let-7a was accomplished utilizing a luciferase-based reporter assay. We conclude that DCLK1 plays a significant master regulatory role in pancreatic tumorigenesis through the regulation of multiple tumor suppressor miRNAs and their downstream pro-tumorigenic pathways. This novel concept of targeting DCLK1 alone has several advantages over targeting single pathway or miRNA-based therapies for PDAC.

Dataset Information

Olfaction regulates organismal proteostasis and longevity via microRNA-dependent signaling.

Publications

Olfaction regulates organismal proteostasis and longevity via microRNA-dependent signaling.

Similar Datasets

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