UPR-inducible miRNAs contribute to stressful situations

Abstract

The endoplasmic reticulum (ER) senses both extracellular and intracellular stresses that can disrupt its ability to facilitate the maturation of proteins destined for secretory pathways. The accumulation of misfolded proteins within the ER triggers an adaptive signaling pathway coined the unfolded protein response (UPR). UPR activation contributes to cell adaptation by reducing the rate of protein translation while increasing the synthesis of chaperones. Although we have gained considerable insight into the mechanisms that regulate gene expression and certain aspects of protein translation, the contribution of miRNAs to UPR-dependent activities has only recently been investigated. Here we highlight recent insights into the contribution of miRNAs to UPR-dependent cellular adaptive responses.

Keywords: ER stress; activating transcription factor 6 (ATF6); apoptosis; inositol-regulated enzyme 1α (IRE1α); microRNA; protein kinase RNA-like endoplasmic reticulum kinase (PERK); unfolded protein response (UPR).

Figure 1. Signal transducers of the UPR

The Unfolded Protein Response (UPR) is triggered under conditions of cellular stress such as energy deprivation, oncogene activation, low oxygen (hypoxia), and viral challenge. Signals from the stressed ER trigger the activation of two transmembrane protein kinases, IRE1α and PERK as well the transmembrane transcription factor ATF6. PERK phosphorylates eIF2α which regulates global protein translation and Nrf2 which regulates expression of anti-oxidant enzymes. IRE1α activates transcription factor Xbp1 via RNase-dependent removal of an intron that prevents efficient translation; ATF6 regulates transcription of chaperone genes. Collectively, PERK, Ire1 and ATF6 signaling modulates cellular adaptation in response to ER stress.

Figure 2. Multiple miRNAs contribute to cell adaptation following UPR activation

ER stress induces IRE1α, PERK, and ATF6. IRE1α degrades precursors of miR-17, miR-34a, miR-96 and miR-125b leading to elevation of their target, caspase-2, and sets the stage for apoptosis. PERK phosphorylates eIF2α, induces ATF4, CHOP and NF-κB. ATF4 induces miR-211, which in turn attenuates CHOP expression and prevents premature apoptosis. Upon expression, CHOP induces miR-708, which in turn targets Rhodopsin and Neuronatin. NF-κB activation is necessary for expression of miR-30-2-3p and moderation of IRE1α-dependent induction of the pro-survival transcription factor, XBP1. PERK also induces Nrf2 (Nuclear Factor-like-2), which along with ATF4, suppresses the miR-106b-25 cluster (miR-106b, miR-25, and miR-93) enabling induction of pro-apoptotic Bim. The third upstream component of ER stress signaling, ATF6, suppresses miR-455, and induces calreticulin which in turn contributes to proper protein folding in heart.