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  • Review Article
  • Published:

Autophagy: controlling cell fate in rheumatic diseases

Nature Reviews Rheumatology volume 12, pages 517–531 (2016)Cite this article

Subjects

A Corrigendum to this article was published on 09 February 2017

This article has been updated

Key Points

  • Autophagy is positively regulated by AMPK, ULK1 and beclin-1 complexes, and negatively regulated by AKT activation, mTORC1 and mTORC2 complexes

  • Autophagy drives cell-fate decisions (including T-cell selection, cell differentiation and apoptosis) and is important in immune cell function and signalling

  • Autophagy is upregulated in rheumatoid arthritis fibroblast-like synoviocytes and systemic lupus erythematosus T cells and plasma cells, increasing their survival and activity

  • Autophagy is downregulated in osteoarthritis chondrocytes (increasing their apoptosis) and systemic sclerosis fibroblasts (increasing their myofibroblastic differentiation)

  • Many therapeutic agents either directly or indirectly target autophagy; however, these must be chosen carefully owing to the multicellular pathophysiology of rheumatic diseases

Abstract

Autophagy, an endogenous process necessary for the turnover of organelles, maintains cellular homeostasis and directs cell fate. Alterations to the regulation of autophagy contribute to the progression of various rheumatic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), osteoarthritis (OA) and systemic sclerosis (SSc). Implicit in the progression of these diseases are cell-type-specific responses to surrounding factors that alter autophagy: chondrocytes within articular cartilage show decreased autophagy in OA, leading to rapid cell death and cartilage degeneration; fibroblasts from patients with SSc have restricted autophagy, similar to that seen in aged dermal fibroblasts; fibroblast-like synoviocytes from RA joints show altered autophagy, which contributes to synovial hyperplasia; and dysregulation of autophagy in haematopoietic lineage cells alters their function and maturation in SLE. Various upstream mechanisms also contribute to these diseases by regulating autophagy as part of their signalling cascades. In this Review, we discuss the links between autophagy, immune responses, fibrosis and cellular fates as they relate to pathologies associated with rheumatic diseases. Therapies in clinical use, and in preclinical or clinical development, are also discussed in relation to their effects on autophagy in rheumatic diseases.

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Figure 1: Regulation of signalling in autophagy.
Figure 2: Dysregulation of autophagy alters cell fate in rheumatic diseases.
Figure 3: Therapeutic modulators of autophagy and associated mechanisms.

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Change history

  • 09 February 2017

    In the article, the sentence “The ubiquitin-like modifier-activating enzyme ATG7 ubiquitylates autophagy protein 5 (ATG5) so that it can form a functional complex with ubiquitin-like protein ATG12” should have appeared as “The ubiquitin-like modifier-activating enzyme ATG7 conjugates autophagy protein 5 (ATG5) with ubiquitin-like protein ATG12 so that it can form a functional complex”. In Figure 1 of the same article, ATG7 was incorrectly shown to be ubiquitylating ATG5, instead of conjugating ATG5 to ATG12. These errors have been corrected in the online version of the article.

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Acknowledgements

The authors' work is supported by the Canadian Institutes of Health Research Operating Grant 126016 to M.K. and the Arthritis Program Grant to M.K. The authors would like to acknowledge the help of Brian Wu in designing figures for this Review.

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Authors and Affiliations

  1. Arthritis Program, Toronto Western Hospital, University Health Network, 399 Bathurst Street, Toronto, M5T 2S8, Ontario, Canada

    Jason S. Rockel & Mohit Kapoor

  2. Division of Genetics and Development, Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, M5T 2R1, Ontario, Canada

    Jason S. Rockel & Mohit Kapoor

  3. Department of Surgery, Department of Laboratory Medicine and Pathobiology, University of Toronto, 686 Bay Street, Toronto, M5G 0A4, Ontario, Canada

    Mohit Kapoor

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Rockel, J., Kapoor, M. Autophagy: controlling cell fate in rheumatic diseases. Nat Rev Rheumatol 12, 517–531 (2016). https://doi.org/10.1038/nrrheum.2016.92

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