An update on autoinflammatory diseases: relopathies
- Author(s)
- Steiner, A; Harapas, CR; Masters, SL; Davidson, S;
- Details
- Publication Year 2018-05-30,Volume 20,Issue #7,Page 39
- Journal Title
- Current Rheumatology Reports
- Publication Type
- Journal Article
- Abstract
- PURPOSE OF REVIEW: The nuclear factor kappaB (NF-kappaB) 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-1beta- and TNF-induced NF-kappaB activation, yet monocytes were hyper-responsive to IL-1beta, 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-kappaB 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-kappaB and of NLRP3 inflammasome activation. HA20 patients present with Behcet-like characteristics or an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype, indicating diverse protein functions. 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.
- Publisher
- Springer
- Research Division(s)
- Inflammation
- PubMed ID
- 29846841
- Publisher's Version
- https://doi.org/10.1007/s11926-018-0749-x
- NHMRC Grants
- NHMRC/1144282, NHMRC/1142354, NHMRC/1099262, NHMRC/1143412,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2018-06-26 12:34:44
Last Modified: 2018-06-26 01:56:37