| MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate messenger RNAs through sequence-specific interactions. miRNAs have recently been shown to exert their regulatory influence during cellular stresses. Endoplasmic reticulum (ER) stress, one example of a cellular stress, stems from an imbalance in the ER's protein folding capacity, oftentimes resulting from such insults as an increase in protein load or expression of misfolding mutant proteins. Consequently, mis- or unfolded proteins accumulate within the ER, which triggers the unfolded protein response (UPR). In mammals, three UPR sensors, IRE1, ATF6, and PERK, detect the folding status of the ER, thus activating transcriptional as well as post-transcriptional programs that lead to adaptation. If ER stress is unmitigated and homeostasis is not restored, the UPR switches from a cytoprotective role to an apoptotic one.;Intriguingly, genome-wide miRNA expression analyses revealed a more complex downstream adaptive network of the UPR. Prolonged ER stress prompted the differential regulation of 11 miRNAs, 8 of which were up-regulated in the presence of ER stress-inducing drugs. The differential expression of only one of those miRNAs, miR-708, demonstrated a dependence on the UPR transcription factor, CHOP. Curiously, mir-708 resides in the intron of Odz4, a gene ambiguously involved in neural development that was also previously characterized as transcriptionally activated by CHOP. The striking co-expression of both miR-708 and Odz4 in the brain and eyes suggested a common physiological function in these tissues. Furthermore, loss- and gain-of-function experiments showed that miR-708 inhibits the expression of rhodopsin, a heavily synthesized multi-spanning transmembrane protein in photoreceptor cells of the eye. In light of this, one can speculate a cytoprotective role for miR-708 whereby it acts to prevent excessive rhodopsin from entering the ER in photoreceptor cell. Thus, miR-708 and its transcriptional activator, CHOP, are implicated in the homeostatic regulation of ER function in the mammalian visual system. |
