TY - JOUR
T1 - MicroRNA-494 Regulates Endoplasmic Reticulum Stress in Endothelial Cells
AU - Chatterjee, Namita
AU - Fraile-Bethencourt, Eugenia
AU - Baris, Adrian
AU - Espinosa-Diez, Cristina
AU - Anand, Sudarshan
N1 - Publisher Copyright:
© Copyright © 2021 Chatterjee, Fraile-Bethencourt, Baris, Espinosa-Diez and Anand.
PY - 2021/7/12
Y1 - 2021/7/12
N2 - 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.
AB - 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.
KW - ER stress
KW - UPR – unfolded protein response
KW - cell stress adaptation
KW - endothelial cells
KW - microRNA
UR - http://www.scopus.com/inward/record.url?scp=85111380971&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85111380971&partnerID=8YFLogxK
U2 - 10.3389/fcell.2021.671461
DO - 10.3389/fcell.2021.671461
M3 - Article
AN - SCOPUS:85111380971
SN - 2296-634X
VL - 9
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 671461
ER -