Tumor necrosis factor receptor-associated periodic syndrome as a model linking autophagy and inflammation in protein aggregation diseases

Tiziana Bachetti, Isabella Ceccherini

Research output: Contribution to journalArticle

Abstract

Autophagy prevents cellular damage by eliminating insoluble aggregates of mutant misfolded proteins, which accumulate under different pathological conditions. Downregulation of autophagy enhances the inflammatory response and thus represents a possible common pathogenic event underlying a number of autoinflammatory syndromes, such as tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). The pathogenesis of other monogenic or complex disorders that display symptoms of excessive inflammation also involve the autophagy pathway. Studies have shown that TRAPS-associated TNFRSF1A mutations induce cytoplasmic retention of the TNFR1 receptor, defective TNF-induced apoptosis, and production of reactive oxygen species (ROS). Furthermore, autophagy impairment may account for the pathogenic effects of TNFRSF1A mutations, thus inducing inflammation in TRAPS. In this review, we summarize the molecular interactions and functional links between autophagy with regard to nuclear factor-kappa B activation, ROS production, and apoptosis. Furthermore, we propose a complex interplay of these pathways as a model to explain the relationship between mutant protein misfolding and inflammation in genetically determined and aggregation-prone diseases. Accordingly, autophagy function should be investigated in all diseases showing an inflammatory component, and for which the molecular pathogenesis is still unclear.

Original languageEnglish
Pages (from-to)583-594
Number of pages12
JournalJournal of Molecular Medicine
Volume92
Issue number6
DOIs
Publication statusPublished - 2014

Fingerprint

Autophagy
Inflammation
Proteins
Mutant Proteins
Reactive Oxygen Species
Apoptosis
Receptors, Tumor Necrosis Factor, Type I
Mutation
NF-kappa B
Tumor Necrosis Factor Receptors
Autosomal Dominant Familial Periodic Fever
Down-Regulation

Keywords

  • Autophagy
  • Inflammation
  • Protein misfolding and aggregation
  • TNF receptor-associated periodic syndrome
  • TNFRSF1A gene

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Genetics(clinical)
  • Medicine(all)

Cite this

@article{0de1c994d0b0421fb56242154648f58e,
title = "Tumor necrosis factor receptor-associated periodic syndrome as a model linking autophagy and inflammation in protein aggregation diseases",
abstract = "Autophagy prevents cellular damage by eliminating insoluble aggregates of mutant misfolded proteins, which accumulate under different pathological conditions. Downregulation of autophagy enhances the inflammatory response and thus represents a possible common pathogenic event underlying a number of autoinflammatory syndromes, such as tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). The pathogenesis of other monogenic or complex disorders that display symptoms of excessive inflammation also involve the autophagy pathway. Studies have shown that TRAPS-associated TNFRSF1A mutations induce cytoplasmic retention of the TNFR1 receptor, defective TNF-induced apoptosis, and production of reactive oxygen species (ROS). Furthermore, autophagy impairment may account for the pathogenic effects of TNFRSF1A mutations, thus inducing inflammation in TRAPS. In this review, we summarize the molecular interactions and functional links between autophagy with regard to nuclear factor-kappa B activation, ROS production, and apoptosis. Furthermore, we propose a complex interplay of these pathways as a model to explain the relationship between mutant protein misfolding and inflammation in genetically determined and aggregation-prone diseases. Accordingly, autophagy function should be investigated in all diseases showing an inflammatory component, and for which the molecular pathogenesis is still unclear.",
keywords = "Autophagy, Inflammation, Protein misfolding and aggregation, TNF receptor-associated periodic syndrome, TNFRSF1A gene",
author = "Tiziana Bachetti and Isabella Ceccherini",
year = "2014",
doi = "10.1007/s00109-014-1150-5",
language = "English",
volume = "92",
pages = "583--594",
journal = "Journal of Molecular Medicine",
issn = "0946-2716",
publisher = "Springer Verlag",
number = "6",

}

TY - JOUR

T1 - Tumor necrosis factor receptor-associated periodic syndrome as a model linking autophagy and inflammation in protein aggregation diseases

AU - Bachetti, Tiziana

AU - Ceccherini, Isabella

PY - 2014

Y1 - 2014

N2 - Autophagy prevents cellular damage by eliminating insoluble aggregates of mutant misfolded proteins, which accumulate under different pathological conditions. Downregulation of autophagy enhances the inflammatory response and thus represents a possible common pathogenic event underlying a number of autoinflammatory syndromes, such as tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). The pathogenesis of other monogenic or complex disorders that display symptoms of excessive inflammation also involve the autophagy pathway. Studies have shown that TRAPS-associated TNFRSF1A mutations induce cytoplasmic retention of the TNFR1 receptor, defective TNF-induced apoptosis, and production of reactive oxygen species (ROS). Furthermore, autophagy impairment may account for the pathogenic effects of TNFRSF1A mutations, thus inducing inflammation in TRAPS. In this review, we summarize the molecular interactions and functional links between autophagy with regard to nuclear factor-kappa B activation, ROS production, and apoptosis. Furthermore, we propose a complex interplay of these pathways as a model to explain the relationship between mutant protein misfolding and inflammation in genetically determined and aggregation-prone diseases. Accordingly, autophagy function should be investigated in all diseases showing an inflammatory component, and for which the molecular pathogenesis is still unclear.

AB - Autophagy prevents cellular damage by eliminating insoluble aggregates of mutant misfolded proteins, which accumulate under different pathological conditions. Downregulation of autophagy enhances the inflammatory response and thus represents a possible common pathogenic event underlying a number of autoinflammatory syndromes, such as tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). The pathogenesis of other monogenic or complex disorders that display symptoms of excessive inflammation also involve the autophagy pathway. Studies have shown that TRAPS-associated TNFRSF1A mutations induce cytoplasmic retention of the TNFR1 receptor, defective TNF-induced apoptosis, and production of reactive oxygen species (ROS). Furthermore, autophagy impairment may account for the pathogenic effects of TNFRSF1A mutations, thus inducing inflammation in TRAPS. In this review, we summarize the molecular interactions and functional links between autophagy with regard to nuclear factor-kappa B activation, ROS production, and apoptosis. Furthermore, we propose a complex interplay of these pathways as a model to explain the relationship between mutant protein misfolding and inflammation in genetically determined and aggregation-prone diseases. Accordingly, autophagy function should be investigated in all diseases showing an inflammatory component, and for which the molecular pathogenesis is still unclear.

KW - Autophagy

KW - Inflammation

KW - Protein misfolding and aggregation

KW - TNF receptor-associated periodic syndrome

KW - TNFRSF1A gene

UR - http://www.scopus.com/inward/record.url?scp=84901592919&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901592919&partnerID=8YFLogxK

U2 - 10.1007/s00109-014-1150-5

DO - 10.1007/s00109-014-1150-5

M3 - Article

C2 - 24706103

AN - SCOPUS:84901592919

VL - 92

SP - 583

EP - 594

JO - Journal of Molecular Medicine

JF - Journal of Molecular Medicine

SN - 0946-2716

IS - 6

ER -