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An Update on Autoinflammatory Diseases: Relopathies

  • Pediatric Rheumatology (S Ozen, Section Editor)
  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The nuclear factor κB (NF-κB) pathway is tightly regulated through multiple posttranslational mechanisms including ubiquitination. Mutations in these regulatory pathways can cause disease and are the focus of this review.

Recent Findings

The linear ubiquitin chain assembly complex (LUBAC) is a trimer made up of HOIL-1L, SHARPIN, and the catalytic subunit HOIP. Loss of function mutations in HOIL-1L and HOIP result in largely overlapping phenotypes, characterized by multi-organ autoinflammation, immunodeficiency, and amylopectinosis. Interestingly, patient fibroblasts exhibited diminished IL-1β- and TNF-induced NF-κB activation, yet monocytes were hyper-responsive to IL-1β, hinting at cell type or target specific roles of LUBAC-mediated ubiquitination. Ubiquitin-driven signaling is counterbalanced by deubiquitinase enzymes (DUBs), such as OTULIN and A20. Hypomorphic mutations in OTULIN result in elevated NF-κB signaling causing an autoinflammatory syndrome. Similarly, patients with high-penetrance heterozygous mutations in the gene encoding A20 (haploinsufficiency of A20 (HA20)) display excessive ubiquitination and increased activity of NF-κB and of NLRP3 inflammasome activation. HA20 patients present with Behçet-like characteristics or an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype, indicating diverse protein functions.

Summary

This review summarizes recent discoveries in the field of NF-kB-related autoinflammatory diseases (relopathies) within the past 3 years and points to several questions that still remain unanswered.

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Acknowledgements

The authors would like to thank the members of the Masters Lab, particularly Dr. Paul Baker and Dr. Fiona Moghaddas, as well as Daniel Simpson (Vince Lab) for discussion and advice on this review. S.L.M acknowledges funding from NHMRC grants (1144282, 1142354 and 1099262), The Sylvia and Charles Viertel Foundation, HHMI-Wellcome International Research Scholarship and Glaxosmithkline. SD acknowledges funding from NHMRC ECF: GNT1143412.

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Authors and Affiliations

  1. Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, 3052, Australia

    Annemarie Steiner, Cassandra R. Harapas, Seth L. Masters & Sophia Davidson

  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, 3010, Australia

    Annemarie Steiner & Seth L. Masters

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  1. Annemarie Steiner
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  2. Cassandra R. Harapas
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Correspondence to Annemarie Steiner or Seth L. Masters.

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Conflict of Interest

Dr. Masters reports grants from NHMRC, grants from Viertel Foundation, grants from HHMI-Wellcome Trust, and grants from Glaxosmithkline, outside the submitted work.

Dr. Davidson reports grants from NHMRC, outside the submitted work.

Drs. Steiner and Harapas declare that they have no conflict of interest.

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This article is part of the Topical Collection on Pediatric Rheumatology

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Steiner, A., Harapas, C.R., Masters, S.L. et al. An Update on Autoinflammatory Diseases: Relopathies. Curr Rheumatol Rep 20, 39 (2018). https://doi.org/10.1007/s11926-018-0749-x

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