GRASP55 and UPR control interleukin-1β aggregation and secretion

Chiritoiu, Marioara; Brouwers, Nathalie; Turacchio, Gabriele; Pirozzi, Marianella; Malhotra, Vivek

doi:http://dx.doi.org/10.1016/j.devcel.2019.02.011

GRASP55 and UPR control interleukin-1β aggregation and secretion

Citation

Chiritoiu M, Brouwers N, Turacchio G, Pirozzi M, Malhotra V. GRASP55 and UPR control interleukin-1β aggregation and secretion. Dev Cell. 2019;49(1):145-55. DOI: 10.1016/j.devcel.2019.02.011

Abstract

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.