Regulation of the unfolded protein response by noncoding RNA

Cells are exposed to various intrinsic and extrinsic stresses in both physiological and pathological conditions. To adapt to those conditions, cells have evolved various mechanisms to cope with the disturbances in protein demand, largely through the unfolded protein response (UPR) in the endoplasmic reticulum (ER), but also through the integrated stress response (ISR). Both responses initiate downstream signaling to transcription factors that, in turn, trigger adaptive programs and/or in the case of prolonged stress, cell death mechanisms. Recently, noncoding RNAs, including microRNA and long noncoding RNA, have emerged as key players in the stress responses. These noncoding RNAs act as both regulators and effectors of the UPR and fine-tune the output of the stress signaling pathways. Although much is known about the UPR and the cross talk that exists between pathways, the contribution of small noncoding RNA has not been fully assessed. Herein we bring together and review the current known functions of noncoding RNA in regulating adaptive pathways in both physiological and pathophysiological conditions, illustrating how they operate within the known UPR functions and contribute to diverse cellular outcomes.