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

  • Cornelia D. Cudrici
  • Richard M. SiegelEmail author


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.


Protein homeostasis Autophagy LC3-associated phagocytosis Autoinflammatory disease Spondyloarthropathy Endoplasmic reticulum (ER) stress response Reactive oxygen species 



Alzheimer disease


Absent in melanoma


AMP-activated protein kinase


Ankylosing spondylitis


Autophagy-related genes


B-cell lymphoma 2


Chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature


cyclic guanosine monophosphate–adenosine monophosphate


cyclic guanosine monophosphate-adenosine monophosphate synthetase


Family interacting protein of 200


Human leukocyte antigen


Interferon regulatory transcription factor


Interferon-stimulated gene


LC3-associated phagocytosis


Microtubule-associated protein light chain 3


Major histocompatibility complex


mammalian target of rapamycin


Neural precursor cell expressed, developmentally down-regulated


Nuclear factor kappa B


Natural killer


NOD-like receptor family pyrin domain containing




Nucleotide-binding oligomerization domain


Parkinson kinase


Protein disulfide isomerase






PTEN-induced putative kinase 1


Reactive oxygen species


STING-associated vasculopathy with onset in infancy


Stimulator of interferon genes


Small ubiquitin-like modifier


TANK binding kinase


Toll-like receptor


Tumor necrosis factor


Target of rapamycin complex


TNF receptor-associated periodic syndrome


The superfamily of tripartite motif-containing


unc-51 like autophagy activating kinase


Unfolded protein response


Ubiquitin–proteasome system


Vacuolar protein sorting


WPP domain–interacting proteins


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Immunoregulation Section, Autoimmunity BranchNIAMS, National Institutes of HealthBethesdaUSA

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