Fine-tuning PERK signaling to control cell fate under stress


PERK is a major sensor of the unfolded protein response controlling cell fate under endoplasmic reticulum (ER) stress. A new study reveals an additional step for optimal PERK signaling, involving the binding of CNPY2 to PERKs luminal domain. The PERK–CNPY2 axis was shown to enhance cell death under ER stress in vivo influence liver disease. Different perturbations to the normal function of the ER lead to abnormal levels of misfolded proteins in that cellular compartment. To cope with ER stress, an evolutionarily conserved signaling pathway known as the unfolded protein response (UPR) is engaged to restore proteostasis. The UPR is initiated by the activation of three types of sensors at the ER membrane—ATF6, IRE1 and PERK—which transduce stress signals from the lumen to the cytosol and nucleus to enforce adaptive pathways1. PERK plays a central role in cell-fate control under ER stress, and recent reports have indicated that abnormal PERK signaling contributes to disease conditions such as neurodegeneration, cancer and diabetes2. However, little is known about PERK regulation and the mechanisms underlying its activation. In this issue of Nature Structural & Molecular Biology, Hong et al.3 identify the ER-located protein canopy homolog 2 (CNPY2) as a novel regulatory factor of PERK that selectively triggers its signaling through a physical interaction (Fig. 1). The study also uncovers the physiological role of CNPY2 in the regulation of the UPR in vivo in the context of liver disease.

Urra H, Hetz C

Nature Structural And Molecular Biology

octubre 05, 2017

DOI: 10.1038/nsmb.3478

Investigador BNI: Claudio Hetz