In this issue of Genes & Development, Hetz and colleagues (pp. 2294–2306) surprisingly show that inhibition of the UPR by knockout of XBP-1 causes a massive increase in autophagy, enhances clearance of superoxide dismutase 1 (SOD1) aggregates, and delays the development of amyotrophic lateral sclerosis. These findings suggest the existence of a homeostatic—if not hormetic—balance between distinct cellular defense mechanisms.
