p38MAPK guards the integrity of endosomal compartments through regulating necrotic death

• Type of Material: Article
• Authors: Jia Yao, Emory University; Svetlana Atasheva, Emory University; Randall Toy, Georgia Institute of Technology; Emmeline L Blanchard, Georgia Institute of Technology; Philip Santangelo, Emory University; Krishnendu Roy, Emory University; Edward Mocarski, Emory University; Dmitry Shayakhmetov, Emory University
• Language: English
• Date: 2022-09-29
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41598-022-20786-4
• Title of Journal or Parent Work: SCIENTIFIC REPORTS
• Volume: 12
• Issue: 1
• Start Page: 16357
• End Page: 16357
• Grant/Funding Information: The National Institutes of Health grant AI124270 (K.R.). The National Institutes of Health grant AI118853 (E.S.M.).; This work was supported by the grants from: The National Institutes of Health grants AI065429, AI107960, and AI126816 (D.M.S).; The National Science Foundation Graduate Research Fellowship Program, Grant No. DGE-1650044 (E.L.B).
• Keywords: CELL-DEATH; NECROPTOSIS; PHOSPHORYLATION; INHIBITION; Science & Technology; Science & Technology - Other Topics; INFLAMMASOME ACTIVATION; NECROSIS; RIPK1; MAP KINASE; KEY REGULATOR; MOLECULAR-MECHANISMS; Multidisciplinary Sciences
• Research Categories: Health Sciences, Immunology; Health Sciences, Medicine and Surgery

Abstract

Pathogens trigger activation of sensors of the innate immune system that initiate molecular signaling enabling appropriate host defense programs. Although recognition of pathogen-specific moieties or PAMPs by specialized receptors of the immune system is well defined for a great number of pathogens, the mechanisms of sensing of pathogen-induced functional perturbations to the host cell remain poorly understood. Here we show that the disruption of endosomal compartments in macrophages by a bacterium or fully synthetic nanoparticles activates stress-response p38MAPK kinase, which triggers execution of cell death of a necrotic type. p38MAPK-mediated necrosis occurs in cells with a compound homozygous deletion of pyroptosis-inducing caspases-1 and -11, apoptotic caspase-8, and necroptosis-inducing receptor-interacting protein kinase-3 (RIPK3), indicating that all of these principal cell death mediators are dispensable for p38MAPK-induced necrosis in response to endosome rupture. p38MAPK-mediated necrosis is suppressed by the receptor-interacting protein kinase 1, RIPK1, and degradation of RIPK1 sensitizes macrophages to necrotic death. Since pathogen-induced cell death of necrotic types is implicated in host defense against infection, our results indicate that functional perturbations in host cells are sensed as a component of the innate immune system.