Control of the inflammasome by the ubiquitin system

Abstract

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.

Suppression of NLRP3 Inflammasome by Erythropoietin via the EPOR/JAK2/STAT3 Pathway Contributes to Attenuation of Acute Lung Injury in Mice

“…is the rapid posttranslational modifications (PTMs) of the inflammasome component NLRP3, which stabilize NLRP3 in an autosuppressed inactive state (Filardy et al, 2016;Barry et al, 2018;Shim and Lee, 2018;Lopez-Castejon, 2019). After priming, the second activation step occurs.…”

Cellular Models and Assays to Study NLRP3 Inflammasome Biology

“…Given the diversity of these signals, it is likely that NLRP3 “senses” a common pathway induced in the cytosolic environment by intracellular processes rather than directly interacting with all these molecules. In all cases, optimal activation of NLRP3 inflammasome requires multiple PTMs such as de-sumoylation [ 18 ], de-ubiquitination [ 19 , 20 ], phosphorylation [ 21 , 22 ], de-phosphorylation, acetylation [ 23 ], and alternative splicing [ 17 , 24 ]. Different PTMs have been accurately described in the literature and are reviewed in [ 13 , 17 ].…”

Linear Ubiquitin Code: Its Writer, Erasers, Decoders, Inhibitors, and Implications in Disorders

“…Upon stimulation through Toll-like receptors (TLRs) by damage-associated molecular patterns (DAMPs) and PAMPs, inflammasomes become oligomerized and activate caspase 1. The ubiquitin system functions as both a negative and positive regulator of inflammasomes [53]. The nucleotide binding and leucine-rich repeat-containing protein 3 (NLRP3) is one of the best characterized inflammasomes.…”