ER stress tolerance is regulated by copper-dependent PERK kinase activity.

Pancreatic/PKR-like endoplasmic reticulum (ER) kinase (PERK) is a kinase that, in response to ER stress, mediates dual homeostatic and pro-apoptotic signaling. Thus, intricate regulation is required for physiological function. Attempts to modulate PERK activity have shown that the determinants of adaptive vs. maladaptive signaling remain ambiguous. Here, with purified protein, we provide evidence that PERK binds copper, identifies residues required for interaction, and demonstrates that copper is necessary for kinase activity. Furthermore, cellular PERK activity can be modulated via copper availability, and this regulatory relationship can be manipulated to dictate ER stress tolerance. Critically, these phenomena translate to phenotypes in vivo, as C. elegans harboring a "PERK-copper mutant" exhibit exacerbated ER-stress sensitivity. The copper-PERK paradigm suggests that copper homeostasis, as a regulator of PERK, may constitute a critical factor in resolving the long-standing ambiguity in endeavors to therapeutically target PERK.