GRASP55 and UPR Control Interleukin-1β Aggregation and Secretion

Signal-sequence-lacking interleukin (IL)-1β, is cleaved by caspase-1 to mature mIL-1β, which is secreted, without entering the endoplasmic reticulum. We report that macrophages of GRASP55 −/− mice are defective in mIL-1β secretion and retain it as intracellular aggregates. Intriguingly, GRASP55 −/− macrophages are defective in the IRE1α branch of the unfolded protein response. This finding fits well with our data that inhibition of IRE1α also impairs mIL-1β secretion and causes its accumulation in intracellular aggregates. PERK inhibition, on the other hand, controls caspase-1-mediated conversion of proIL-1β to mIL-1β. These findings reveal translation-independent functions of PERK and IRE1α: PERK controls the production of mIL-1β, which is then followed by GRASP55 and IRE1α activity to keep mIL-1β in a secretion-competent form. Chiritoiu et al. report the key control steps that are necessary for mature interleukin (IL)-1β secretion by lipopolysaccharide-activated primary mouse macrophages. The ER-associated unfolded protein response along with the Golgi-attached protein GRASP55 function together to ensure that cytoplasmic mIL-1β does not aggregate and is secreted in the right quantities.