Control of the inflammasome by the ubiquitin system

• Published in: The FEBS journal Vol. 287; no. 1; pp. 11 - 26
• Main Author: Lopez‐Castejon, Gloria
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-01-2020; John Wiley and Sons Inc
• Subjects: Activation; Aging; Alzheimer's disease; Animals; Apoptosis; Assembly; Caspase; caspase‐1; Cell death; Chronic obstructive pulmonary disease; Cytokines; deubiquitinases; E3 enzymes; Homeostasis; Humans; Immune system; inflammasome; Inflammasomes; Inflammation; Inflammation - immunology; Inflammation - metabolism; Inflammation - pathology; Inflammatory response; Interleukins; interleukin‐1; Macrophages; Metabolic disorders; Neurodegenerative diseases; NLRP3; Pattern recognition; Pattern recognition receptors; post‐translational modifications; Pyroptosis; Regulators; Review; Toxins; Ubiquitin; Ubiquitin - metabolism; Ubiquitination; deubiquitinases; interleukin-1; inflammation; inflammasome; NLRP3; post-translational modifications; E3 enzymes; caspase-1; ubiquitin
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.15118

Inflammation is the body’s response to danger. One of the first immune cell types to encounter danger is the macrophage. Macrophages sense danger signals such as extracellular ATP or bacterial toxins, derived from tissue damage or infection, and initiate the activation of an intracellular molecular complex called the inflammasome. The inflammasome consists of a cytosolic pattern recognition receptor, an adaptor molecule ASC (apoptosis‐associated speck‐like protein containing a CARD) and the protease caspase‐1. Assembly of the complex leads to the cleavage and activation of caspase‐1 that triggers processing and release of the cytokines interleukin (IL)‐1β and IL‐18, and ultimately cell death via the process of pyroptosis. The ability to sense and respond to danger appropriately is critical for maintaining immune homeostasis. Dysregulation of inflammasomes contributes to the progression of chronic diseases prevalent in the ageing population, such as Alzheimer’s disease, COPD and metabolic disease; hence, it is critical that activation of the inflammatory response and inflammasome activation are tightly regulated. Post‐translational modifications (PTMs) such as ubiquitination have recently emerged as important regulators of inflammasome assembly. However, the mechanisms by which PTMs regulate the inflammasome are still not understood. This review aims to summarize our knowledge to date on how the ubiquitin system controls inflammasome activation and where this area of research is heading.
Inflammasome assembly is essential to mount an appropriate inflammatory response against danger signals that constitute a threat to the body. Despite the importance of inflammasomes in disease, the mechanism underpinning the regulation of these molecular complexes still remains unclear. This review will discuss how the post‐translational modification ubiquitin and the different members of the ubiquitin system contribute to the control of these molecular complexes.