Disruption of Protein Homeostasis and Activation of Cellular Stress Pathways in Autoinflammation

Abstract

In addition to being a critical part of host defense against pathogens, the inflammatory response can also be triggered by a number of perturbations to cellular homeostasis, including responses to protein misfolding and endoplasmic reticulum (ER) stress. Physiologically, these responses can lead to activation of tissue repair pathways, but when not properly regulated, these stress response pathways can lead to chronic inflammation. ER stress and other inflammatory pathways triggered by misfolded proteins have been implicated in the pathogenesis of several monogenic autoinflammatory diseases, and also may play a role in other conditions such as neurodegenerative diseases, where increasing evidence has accumulated about the contribution of inflammation to disease pathogenesis. Alterations in protein homeostasis can trigger autoinflammatory diseases in a number of ways, including (1) a pathogenic protein is itself misfolded, primarily activating inflammatory signaling pathways, as with the mutant tumor necrosis factor receptor 1 (TNFR1) protein in TNF receptor-associated periodic syndrome (TRAPS), or triggering an intracellular ER stress response, such as the human leukocyte antigen (HLA)-B27 protein in spondylarthropathies; (2) inflammatory responses can also be triggered by extracellular misfolded proteins, and (3) genetic defects in protein homeostasis pathways which lead to inflammatory diseases. Examples of this mechanism are proteasome mutations in chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature (CANDLE) and related syndromes, and variants in the gene encoding ATG16L which reduce the efficiency of autophagy and related secretory pathways in inflammatory bowel disease.