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Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

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Abstract

Cells have a number of mechanisms to maintain protein homeostasis, including proteasome-mediated degradation of ubiquitinated proteins and autophagy, a regulated process of “self-eating” where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by toll-like receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses. Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.

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Acknowledgments

The authors would like to thank the Leeds Teaching Hospitals Special Trustees (9/R01/2002), Arthritis Research UK (grant 19269) and the NIHR-Leeds Musculoskeletal Biomedical Research Unit who funded McD and the Wolfson Foundation who funded an intercalated degree research scholarship for SH. RMS and AA are supported by the NIAMS intramural research program, and AA is an NIH UGSP scholar.

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Authors and Affiliations

  1. Immunoregulation Section, Autoimmunity Branch, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Amma F. Agyemang & Richard M. Siegel

  2. National Institute for Health Research–Leeds Musculoskeletal Biomedical Research Unit (NIHR-LMBRU) and Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), St James University, Wellcome Trust Brenner Building, Beckett Street, Leeds, LS9 7TF, West Yorkshire, UK

    Stephanie R. Harrison & Michael F. McDermott

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  1. Amma F. Agyemang
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  2. Stephanie R. Harrison
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  3. Richard M. Siegel
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  4. Michael F. McDermott
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Correspondence to Richard M. Siegel or Michael F. McDermott.

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This article is a contribution to the Special Issue on The Inflammasome and Autoinflammatory Diseases - Guest Editors: Seth L. Masters, Tilmann Kallinich and Seza Ozen

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Agyemang, A.F., Harrison, S.R., Siegel, R.M. et al. Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond. Semin Immunopathol 37, 335–347 (2015). https://doi.org/10.1007/s00281-015-0496-2

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