An Update on Autoinflammatory Diseases: Relopathies.

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• The nuclear factor κB (NF-κB) pathway is critical for immune responses and is tightly regulated by posttranslational modifications, especially ubiquitination.
• Dysregulation of NF-κB signaling due to mutations in its regulatory components can result in various diseases.

Purpose of the Study:

• This review focuses on the role of ubiquitination in regulating the NF-κB pathway and its implications in disease.
• It summarizes recent advancements in understanding NF-κB-related autoinflammatory diseases (relopathies) over the past three years.

Main Methods:

• The review synthesizes findings from recent scientific literature on NF-κB pathway regulation and associated autoinflammatory conditions.
• It highlights the impact of mutations in key regulatory proteins such as the linear ubiquitin chain assembly complex (LUBAC), OTULIN, and A20.

Main Results:

• Loss-of-function mutations in LUBAC components (HOIL-1L, HOIP) lead to autoinflammation, immunodeficiency, and amylopectinosis, with cell-type specific effects on NF-κB activation.
• Mutations in deubiquitinase enzymes, including OTULIN and A20 (haploinsufficiency of A20 - HA20), result in elevated NF-κB signaling, autoinflammatory syndromes, and phenotypes resembling Behçet's disease or ALPS.

Conclusions:

• Aberrant ubiquitination of NF-κB pathway components is a significant driver of autoinflammatory diseases.
• Further research is needed to address outstanding questions regarding the precise mechanisms and therapeutic strategies for these complex genetic disorders.