Regulators of A20 (TNFAIP3): new drug-able targets in inflammation

Abstract

Persistent activation of the transcription factor Nuclear factor-κB (NF-κB) is central to the pathogenesis of many inflammatory disorders, including those of the lung such as cystic fibrosis (CF), asthma, and chronic obstructive pulmonary disease (COPD). Despite recent advances in treatment, management of the inflammatory component of these diseases still remains suboptimal. A20 is an endogenous negative regulator of NF-κB signaling, which has been widely described in several autoimmune and inflammatory disorders and more recently in terms of chronic lung disorders. However, the underlying mechanism for the apparent lack of A20 in CF, COPD, and asthma has not been investigated. Transcriptional regulation of A20 is complex and requires coordination of different transcription factors. In this review we examine the existing body of research evidence on the regulation of A20, concentrating on pulmonary inflammation. Special focus is given to the repressor downstream regulatory element antagonist modulator (DREAM) and its nuclear and cytosolic action to regulate inflammation. We provide evidence that would suggest the A20-DREAM axis to be an important player in (airway) inflammatory responses and point to DREAM as a potential future therapeutic target for the modification of phenotypic changes in airway inflammatory disorders. A schematic summary describing the role of DREAM in inflammation with a focus on chronic lung diseases as well as the possible consequences of altered DREAM expression on immune responses is provided.

Transcriptogram analysis reveals relationship between viral titer and gene sets responses during Corona-virus infection

“…We have highlighted in navy blue the expression of EGR3 and TWIST1, the two genes whose differential expression presents the largest fold changes in cluster B. TWIST1 negatively regulates the NF-κB protein complex. TWIST1 is thus anti-inflammatory [24]. The variation in the TWIST1 time series in Error!…”

“…Fig. 5, bottom-left panel (olive green) highlights the differential expression evolution of JUN and TNFAIP3 from cluster B. JUN encodes c-Jun, a protein that participates in the transcription-factor complex "Activator Protein-1" (AP-1) that has complex context-dependent behaviors [22]. In epithelial cells AP-1 components (containing c-Jun) may participate in apoptosis or cell proliferation.…”

“…TNFAIP3 is thus a negative regulator of inflammation and is known to be rapidly induced after Toll-like receptors interact with a pathogen or respond to TNF-α or IL-1 cytokines [22]. The bottom-left panel in Fig.…”

The Ubiquitin System and A20: Implications in Health and Disease

“…An increased appreciation of ubiquitin-mediated regulation of key biological processes in health and disease states has led to the discovery of A20 as a critical modulator of cellular homeostasis (Hu and Sun 2016; Malynn and Ma 2019; Martens and van Loo 2020; Priem et al 2020). Genome-wide association studies identified somatic mutations, deletions, and/or aberrant expression of A20 in rheumatoid arthritis, diabetes, SLE, inflammatory bowel disease, psoriasis, Sjögren syndrome, coronary artery disease, multiple sclerosis, cystic fibrosis, and asthma (Boonyasrisawat et al 2007; Ma and Malynn 2012; Momtazi et al 2019; Martens and van Loo 2020). While A20 function is fairly well-characterized in several tissues, only recently did it begin to receive attention as a regulator of oral mucosa homeostasis.…”

“…In addition, aberrant function of enzymes involved in ubiquitin regulation oftentimes contribute to the onset and progression of several disorders. Particularly, abnormal expression and/or function of ubiquitin-editing protein A20 (tumor necrosis factor α–induced protein 3 or TNFAIP3) has been associated with chronic inflammation and tissue damage, contributing to the immunopathology of multiple human autoimmune and inflammatory diseases, including diabetes and cancer, as well as pulmonary, neurological, skin, and gastrointestinal disorders (Fukaya et al 2016; Zhou et al 2016; Aeschlimann et al 2018; Kadowaki et al 2018; Devos et al 2019; Momtazi et al 2019). Recent evidence also reveals the ubiquitin system and A20 as a critical regulator in the oral cavity and particularly in periodontal disease pathogenesis (Hong et al 2016; Zhou et al 2016; Crump et al 2017; Li et al 2019; 2020; Yan et al 2020).…”