GRASP55 and UPR Control Interleukin-1β Aggregation and Secretion

Signal-sequence-lacking interleukin (IL)-1 beta, is cleaved by caspase-1 to mature mIL-1 beta, which is secreted, without entering the endoplasmic reticulum. We report that macrophages of GRASP55(-/-) mice are defective in mIL-1 beta secretion and retain it as intracellular aggregates. Intriguingly, GRASP55(-/-) macrophages are defective in the IRE1 alpha branch of the unfolded protein response. This finding fits well with our data that inhibition of IRE1 alpha also impairs mIL-1 beta secretion and causes its accumulation in intracellular aggregates. PERK inhibition, on the other hand, controls caspase-1-mediated conversion of proIL-1 beta to mIL-1 beta. These findings reveal translation-independent functions of PERK and IRE1 alpha: PERK controls the production of mIL-1 beta, which is then followed by GRASP55 and IRE1 alpha activity to keep mIL-1 beta in a secretion-competent form.