2. Academic Validation
  3. GRASP55 and UPR Control Interleukin-1β Aggregation and Secretion

GRASP55 and UPR Control Interleukin-1β Aggregation and Secretion

  • Dev Cell. 2019 Apr 8;49(1):145-155.e4. doi: 10.1016/j.devcel.2019.02.011.
Marioara Chiritoiu 1,  Nathalie Brouwers 1,  Gabriele Turacchio 2,  Marinella Pirozzi 2,  Vivek Malhotra 3
Affiliations

Affiliations

  • 1 Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain.
  • 2 Institute of Protein Biochemistry, National Research Council, Via Pietro Castellino 111, Naples 80131, Italy.
  • 3 Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluis Companys 23, Barcelona 08010, Spain. Electronic address: vivek.malhotra@crg.eu.
PMID: 30880003 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.

Keywords

GRASP; interleukin-1β (IL-1β); unconventional protein secretion (UPS); unfolded protein response (UPR).

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