MicroRNA-494 Regulates Endoplasmic Reticulum Stress in Endothelial Cells

Namita Chatterjee, Eugenia Fraile-Bethencourt, Adrian Baris, Cristina Espinosa-Diez, Sudarshan Anand

Research output: Contribution to journalArticlepeer-review

Abstract

Defects in stress responses are important contributors in many chronic conditions including cancer, cardiovascular disease, diabetes, and obesity-driven pathologies like non-alcoholic steatohepatitis (NASH). Specifically, endoplasmic reticulum (ER) stress is linked with these pathologies and control of ER stress can ameliorate tissue damage. MicroRNAs have a critical role in regulating diverse stress responses including ER stress. Here, we show that miR-494 plays a functional role during ER stress. Pharmacological ER stress inducers (tunicamycin (TCN) and thapsigargin) and hyperglycemia robustly increase the expression of miR-494 in vitro. ATF6 impacts the primary miR-494 levels whereas all three ER stress pathways are necessary for the increase in mature miR-494. Surprisingly, miR-494 pretreatment dampens the induction and magnitude of ER stress in response to TCN in endothelial cells and increases cell viability. Conversely, inhibition of miR-494 increases ER stress de novo and amplifies the effects of ER stress inducers. Using Mass Spectrometry (TMT-MS) we identified 23 proteins that are downregulated by both TCN and miR-494 in cultured human umbilical vein endothelial cells. Among these, we found 6 transcripts which harbor a putative miR-494 binding site. We validated the anti-apoptotic gene BIRC5 (survivin) and GINS4 as targets of miR-494 during ER stress. In summary, our data indicates that ER stress driven miR-494 may act in a feedback inhibitory loop to dampen downstream ER stress signaling.

Original languageEnglish (US)
Article number671461
JournalFrontiers in Cell and Developmental Biology
Volume9
DOIs
StatePublished - Jul 12 2021
Externally publishedYes

Keywords

  • ER stress
  • UPR – unfolded protein response
  • cell stress adaptation
  • endothelial cells
  • microRNA

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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