Endoplasmic reticulum (ER) stress promotes the unfolded protein response (UPR), which is characterized by induction of the IRE1, PERK and ATF6 effector proteins. PERK promotes both survival and apoptosis, but it remains unclear how these activities are balanced. Diehl and colleagues now report that a PERK-induced microRNA has a key role in this process (Mol. Cell http://doi.org/jhq; 2012).

The authors found that ER stress upregulated miR-211 expression in a PERK- and ATF4-dependent manner. PERK and ATF4 are also known to induce expression of the pro-apoptotic protein CHOP. Intriguingly, miR-211 decreased CHOP expression in response to ER stress, but not by targeting CHOP mRNA. Instead, miR-211 bound CHOP promoter regions and elicited H3K27me3 methylation marks and Ago1 accumulation to silence CHOP expression.

Inhibition of miR-211 increased ER-stress-induced apoptosis in wild-type, but not in CHOP-null, cells. This relationship might also be relevant in cancer, as miR-211 expression was elevated in mouse mammary tumours and correlated inversely with CHOP expression. Higher miR-211 expression was also observed in primary human lymphomas compared to normal B lymphocytes. The authors conclude that PERK–ATF4 signalling promotes accumulation of CHOP but also miR-211, which in turn limits CHOP expression and increases survival.