Neutralizing antibodies to interferon beta: Assessment of their clinical and radiographic impact: An evidence report: Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology

Abstract

<h3>Abstract</h3> 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. ER stress inducers (tunicamycin &amp; thapsigargin) robustly increase the expression of miR-494 <i>in vitro</i> in an ATF6 dependent manner. Surprisingly, miR-494 pretreatment dampens the induction and magnitude of ER stress in response to tunicamycin in endothelial cells. Conversely, inhibition of miR-494 increases ER stress <i>de novo</i> and amplifies the effects of ER stress inducers. Using Mass Spectrometry (TMT-MS) we identified 23 proteins that are downregulated by both tunicamycin and miR-494. Among these, we found 6 transcripts which harbor a putative miR-494 binding site. We validated the anti-apoptotic gene <i>BIRC5</i> (survivin) as one of the targets of miR-494 during ER stress. Finally, induction of ER stress <i>in vivo</i> increases miR-494 expression in the liver. Pretreatment of mice with a miR-494 plasmid via hydrodynamic injection decreased ER stress in response to tunicamycin in part by decreasing inflammatory chemokines and cytokines. In summary, our data indicates that ER stress driven miR-494 may act in a feedback inhibitory loop to dampen downstream ER stress signaling. We propose that RNA-based approaches targeting miR-494 or its targets may be attractive candidates for inhibiting ER stress dependent pathologies in human disease.