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

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Textbook of Autoinflammation

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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.

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Abbreviations

AD:

Alzheimer disease

AIM:

Absent in melanoma

AMPK:

AMP-activated protein kinase

AS:

Ankylosing spondylitis

ATG:

Autophagy-related genes

Bcl-2:

B-cell lymphoma 2

CANDLE:

Chronic atypical neutrophilic dermatitis with lipodystrophy and elevated temperature

cGAMP:

cyclic guanosine monophosphate–adenosine monophosphate

cGAS:

cyclic guanosine monophosphate-adenosine monophosphate synthetase

FIP200:

Family interacting protein of 200

HLA:

Human leukocyte antigen

IRF:

Interferon regulatory transcription factor

ISG:

Interferon-stimulated gene

LAP:

LC3-associated phagocytosis

LC3:

Microtubule-associated protein light chain 3

MHC:

Major histocompatibility complex

mTOR:

mammalian target of rapamycin

NEDD:

Neural precursor cell expressed, developmentally down-regulated

NF-κB:

Nuclear factor kappa B

NK:

Natural killer

NLRP:

NOD-like receptor family pyrin domain containing

NMDA:

N-methyl-d-aspartate

NOD:

Nucleotide-binding oligomerization domain

PARKIN:

Parkinson kinase

PDA:

Protein disulfide isomerase

PE:

Phosphatidylethanolamine

PI:

Phosphatidylinositol

PINK:

PTEN-induced putative kinase 1

ROS:

Reactive oxygen species

SAVI:

STING-associated vasculopathy with onset in infancy

STING:

Stimulator of interferon genes

SUMO:

Small ubiquitin-like modifier

TBK:

TANK binding kinase

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

TORC:

Target of rapamycin complex

TRAPS:

TNF receptor-associated periodic syndrome

TRIM:

The superfamily of tripartite motif-containing

ULK:

unc-51 like autophagy activating kinase

UPR:

Unfolded protein response

UPS:

Ubiquitin–proteasome system

VPS:

Vacuolar protein sorting

WIP:

WPP domain–interacting proteins

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Authors and Affiliations

  1. Immunoregulation Section, Autoimmunity Branch, NIAMS, National Institutes of Health, Bethesda, MD, USA

    Cornelia D. Cudrici & Richard M. Siegel

Authors
  1. Cornelia D. Cudrici
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  2. Richard M. Siegel
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Corresponding author

Correspondence to Richard M. Siegel .

Editor information

Editors and Affiliations

  1. Pediatric Rheumatology Unit, Shaare Zedek Medical Center and Hebrew University, Jerusalem, Israel

    Philip J. Hashkes

  2. Department Paediatrics, Division of Rheumatology, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

    Ronald M. Laxer

  3. Department of Internal Medicine, Radboudumc Expertisecenter for Immunodeficiency and Autoinflammation, Radboud University Medical Center, Nijmegen, The Netherlands

    Anna Simon

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Cudrici, C.D., Siegel, R.M. (2019). Disruption of Protein Homeostasis and Activation of Cellular Stress Pathways in Autoinflammation. In: Hashkes, P., Laxer, R., Simon, A. (eds) Textbook of Autoinflammation. Springer, Cham. https://doi.org/10.1007/978-3-319-98605-0_8

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  • DOI: https://doi.org/10.1007/978-3-319-98605-0_8

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-98604-3

  • Online ISBN: 978-3-319-98605-0

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