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

  • Cornelia D. Cudrici
  • Richard M. SiegelEmail author
Chapter

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.

Keywords

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

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

References

  1. 1.
    van Deventer S, Neefjes J. The immunoproteasome cleans up after inflammation. Cell. 2010;142(4):517–8.PubMedCrossRefGoogle Scholar
  2. 2.
    Green DR, Levine B. To be or not to be? How selective autophagy and cell death govern cell fate. Cell. 2014;157(1):65–75.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Martinez J, Malireddi RK, Lu Q, et al. Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins. Nat Cell Biol. 2015;17(7):893–906.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Martinez J, Cunha LD, Park S, et al. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature. 2016;533(7601):115–9.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Saitoh T, Akira S. Regulation of inflammasomes by autophagy. J Allergy Clin Immunol. 2016;138(1):28–36.PubMedCrossRefGoogle Scholar
  6. 6.
    Shi CS, Shenderov K, Huang NN, et al. Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012;13(3):255–63.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Kimura T, Jain A, Choi SW, et al. TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J Cell Biol. 2015;210(6):973–89.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Harris J, Hartman M, Roche C, et al. Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J Biol Chem. 2011;286(11):9587–97.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Harris J. Autophagy and IL-1 family cytokines. Front Immunol. 2013;4:83.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Saitoh T, Fujita N, Jang MH, et al. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008;456(7219):264–8.PubMedCrossRefGoogle Scholar
  11. 11.
    Nakahira K, Haspel JA, Rathinam VA, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. 2011;12(3):222–30.PubMedCrossRefGoogle Scholar
  12. 12.
    Sun L, Wu J, Du F, Chen X, Chen Z. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science (New York, NY). 2013;339(6121):786–91.CrossRefGoogle Scholar
  13. 13.
    Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371(6):507–18.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Moretti J, Roy S, Bozec D, et al. STING senses microbial viability to orchestrate stress-mediated autophagy of the endoplasmic reticulum. Cell. 2017;171(4):809–23 e13.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Konno H, Konno K, Barber G. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell. 2013;155(3):688–98.PubMedCrossRefGoogle Scholar
  16. 16.
    McDermott MF, Aksentijevich I, Galon J, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97(1):133–44.PubMedCrossRefGoogle Scholar
  17. 17.
    Bulua AC, Simon A, Maddipati R, et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208(3):519–33.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Bachetti T, Chiesa S, Castagnola P, et al. Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS). Ann Rheum Dis. 2013;72(6):1044–52.PubMedCrossRefGoogle Scholar
  19. 19.
    Simon A, Park H, Maddipati R, et al. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc Natl Acad Sci U S A. 2010;107(21):9801–6.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Dickie LJ, Aziz AM, Savic S, et al. Involvement of X-box binding protein 1 and reactive oxygen species pathways in the pathogenesis of tumour necrosis factor receptor-associated periodic syndrome. Ann Rheum Dis. 2012;71(12):2035–43.PubMedCrossRefGoogle Scholar
  21. 21.
    De Benedetti F, Gattorno M, Anton J, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med. 2018;378(20):1908–19.PubMedCrossRefGoogle Scholar
  22. 22.
    Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008;456(7219):259–63.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Braun J, Sieper J. Ankylosing spondylitis. Lancet. 2007;369(9570):1379–90.PubMedCrossRefGoogle Scholar
  24. 24.
    Allen RL, Trowsdale J. Recognition of classical and heavy chain forms of HLA-B27 by leukocyte receptors. Curr Mol Med. 2004;4(1):59–65.PubMedCrossRefGoogle Scholar
  25. 25.
    Kollnberger S, Bowness P. The role of B27 heavy chain dimer immune receptor interactions in spondyloarthritis. Adv Exp Med Biol. 2009;649:277–85.PubMedCrossRefGoogle Scholar
  26. 26.
    Goodall JC, Wu C, Zhang Y, et al. Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. Proc Natl Acad Sci U S A. 2010;107(41):17698–703.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Colbert RA, Tran TM, Layh-Schmitt G. HLA-B27 misfolding and ankylosing spondylitis. Mol Immunol. 2014;57(1):44–51.PubMedCrossRefGoogle Scholar
  28. 28.
    Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012;18(7):1069–76.PubMedCrossRefGoogle Scholar
  29. 29.
    Taurog JD, Chhabra A, Colbert RA. Ankylosing spondylitis and axial spondyloarthritis. N Engl J Med. 2016;374(26):2563–74.PubMedCrossRefGoogle Scholar
  30. 30.
    Martinon F, Chen X, Lee AH, Glimcher LH. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010;11(5):411–8.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Scheper W, Hoozemans JJ. The unfolded protein response in neurodegenerative diseases: a neuropathological perspective. Acta Neuropathol. 2015;130(3):315–31.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Costa RO, Lacor PN, Ferreira IL, et al. Endoplasmic reticulum stress occurs downstream of GluN2B subunit of N-methyl-d-aspartate receptor in mature hippocampal cultures treated with amyloid-beta oligomers. Aging Cell. 2012;11(5):823–33.PubMedCrossRefGoogle Scholar
  33. 33.
    Uehara T, Nakamura T, Yao D, et al. S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature. 2006;441(7092):513–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Salminen A, Kauppinen A, Suuronen T, Kaarniranta K, Ojala J. ER stress in Alzheimer’s disease: a novel neuronal trigger for inflammation and Alzheimer’s pathology. J Neuroinflammation. 2009;6:41.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Masters SL, Dunne A, Subramanian SL, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol. 2010;11(10):897–904.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007;356(15):1517–26.PubMedCrossRefGoogle Scholar
  37. 37.
    Makley LN, McMenimen KA, DeVree BT, et al. Pharmacological chaperone for alpha-crystallin partially restores transparency in cataract models. Science. 2015;350(6261):674–7.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat Rev Drug Discov. 2017;16(7):487–511.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Rubinsztein DC, Codogno P, Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov. 2012;11(9):709–30.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Cromm PM, Crews CM. Targeted protein degradation: from chemical biology to drug discovery. Cell Chem Biol. 2017;24(9):1181–90.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Agyemang AF, Harrison SR, Siegel RM, McDermott MF. Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond. Semin Immunopathol. 2015;37(4):335–47.PubMedCrossRefGoogle Scholar
  42. 42.
    Park H, Bourla AB, Kastner DL, Colbert RA, Siegel RM. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol. 2012;12(8):570–80.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

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

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