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Proteasomes in Autoinflammation

  • Anja Brehm
  • Frédéric Ebstein
  • Elke KrügerEmail author
Chapter

Abstract

The cellular proteostasis network integrates all signals controlling protein synthesis, folding, trafficking, and clearance machineries in multiple subcellular compartments to maintain the integrity of the proteome and to ensure the survival of cells and tissues under varying proteotoxic insults. We here review the proteostasis network that controls the adaptation of the ubiquitin proteasome system (UPS) to cellular demands and its perturbations in autoinflammation. Proteotoxic stress of various physiological origins such as inflammation can be typically counteracted by the shut-down of global protein translation, or the up-regulation of protein quality control and degradation machineries including stress specific sets of ubiquitin-conjugation and deconjugation factors as well as alternative proteasome isoforms. The loss of controlled adaptation and/or impairment of proteasome function represent a hallmark of various proteinopathies including proteasome associated autoinflammatory syndromes (PRAAS) , which are accompanied by oxidative stress and induction of endoplasmic reticulum (ER) stress. A common and surprising feature of such diseases is the initiation of chronic inflammation under pathogen-free conditions through the release of various mediators, particularly type I interferon (IFN). Recent work in this field has highlighted a possible role of ER-membrane located signaling cascades originating from TCF11/Nrf1 as well as the PERK and IRE1α arms of the unfolded protein response (UPR) in this process. Their precise implication in the pathogenesis of proteinopathies as well as their relevance for the design of novel drug targets will be discussed.

Keywords

Proteostasis Ubiquitin Proteasome Inflammation Unfolded protein response Proteinopathy Interferonopathy PRAAS 

Abbreviations

ALIS

Aggresome-like induced structures

ARE

Antioxidant response elements

ATF

Activated transcription factor

CANDLE

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature

CHOP

C/EBP-homologous protein 10

COX

Cyclooxygenase

CP

Core particle

DALIS

Dendritic aggresome-like induced structures

DC

Dendritic cell

DDI2

DNA damage-inducible protein homolog 2

DRiP

Defective ribosomal product

DUB

Deubiquitinating enzyme

eIF2

eukaryotic translation initiation factor 2

ER

Endoplasmic reticulum

ERAD

ER-associated degradation

GADD34

Growth arrest and DNA damage-inducible protein 34

IFN

Interferon

IP

Immunoproteasome

IRE-1

Inositol-requiring protein 1

IRF3

Interferon regulatory factor 3

ISG

Interferon-stimulated gene

JMP

Joint contractures muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy

KLICK

Keratosis linearis with ichthyosis congenita and sclerosing keratoderma syndrome

MHC

Major histocompatibility complex

NOX

NADPH oxidase

NNS

Nakajo-Nishimura syndrome

Nrf1

Nuclear factor erythroid 2-related factor 1

OASL

2′-5′-Oligoadenylate synthase-like protein

PA200

Proteasome activator 200

PA28

Proteasome activator 28

PAC

Proteasome assembly chaperone

PAMP

Pathogen-associated molecular pattern

PERK

Protein kinase R-like endoplasmic reticulum kinase

PKR

Protein kinase R

POMP

Proteasome maturation protein

PRAAS

Proteasome-associated autoinflammatory syndrome

PRR

Pathogen recognition receptor

RIDD

IRE1α-dependent decay

RIG-1

Retinoic acid-inducible gene 1 protein

RNS

Reactive-nitrogen species

ROS

Reactive oxygen species

RP

Regulatory particle

Rpn

Regulatory particle non-ATPase subunit

SP

Standard proteasome

TCF11

Transcription factor 11

UPR

Unfolded protein response

UPS

Ubiquitin-proteasome system

XBP-1

X-box-binding protein 1

XO

Xanthine oxidase

Notes

Acknowledgements

This work was supported by the German Research Foundation and the Fritz-Thyssen-Foundation.

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Institut für BiochemieCharité Universitätsmedizin BerlinBerlinGermany
  2. 2.Institut für Medizinische Biochemie und MolekularbiologieUniversitätsmedizin GreifswaldGreifswaldGermany

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