Importance of Deubiquitination in Macrophage-Mediated Viral Response and Inflammation

Abstract

Ubiquitination and deubiquitination play a fundamental role in the signaling pathways associated with innate and adaptive immune responses. Macrophages are key sentinels for the host defense, triggering antiviral and inflammatory responses against various invading pathogens. Macrophages recognize the genetic material of these pathogens as pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) through the activation of its pattern recognition receptors (PRRs), initiating the cascade of immune signaling, which leads to the production of pro- and anti-inflammatory cytokines that initiates the appropriate immune response. Macrophage-mediated immune response is highly regulated and tightly controlled by the ubiquitin system since its abnormal activation or dysregulation may result in the severe pathogenesis of numerous inflammatory and autoimmune diseases. Deubiquitinating enzymes (DUBs) play a crucial role in reversing the ubiquitination and controlling the magnitude of the immune response. During infection, pathogens manipulate the host defense system by regulating DUBs to obtain nutrients and increase proliferation. Indeed, the regulation of DUBs by small molecule inhibitors has been proposed as an excellent way to control aberrant activation of immune signaling molecules. This review is focused on the complex role of DUBs in macrophage-mediated immune response, exploring the potential use of DUBs as therapeutic targets in autoimmune and inflammatory diseases by virtue of small molecule DUB inhibitors.

Construction of the coexpression network involved in the pathogenesis of thyroid eye disease via bioinformatics analysis

“…Ubiquitination is believed to be involved in the regulation of almost all life activities, including cell cycle, proliferation, apoptosis, gene expression, transcription regulation, inflammatory immunity, etc. Several studies have found that ubiquitination has an important regulatory role in autoimmune diseases [31][32][33]. Ubiquitination controls the development, activation and differentiation of T cells and maintains an effective adaptive immune response to pathogens and immune tolerance to self-tissues.…”

NOD1 is super-activated through spatially-selective ubiquitination by the Salmonella effector SspH2

“…NLRP3 inflammasome activity is regulated by ubiquitination. Ubiquitination via Pellino2 (35), and de-ubiquitination on the NLRP3 LRR domain via BRCC3 (36,37) have been shown to activate NLRP3. Alternatively, de-ubiquitination via IRAK1 (35), and ubiquitination by TRIM31 have also been shown to decrease NLRP3 activity by inducing proteasomal degradation in the case of the latter (38).…”

“…Ubiquitination via Pellino2 (35), and de-ubiquitination on the NLRP3 LRR domain via BRCC3 (36,37) have been shown to activate NLRP3. Alternatively, de-ubiquitination via IRAK1 (35), and ubiquitination by TRIM31 have also been shown to decrease NLRP3 activity by inducing proteasomal degradation in the case of the latter (38). Notably, the bacterial E3 ligase, YopM, has been observed to decrease NLRP3 activation via K63-linked ubiquitination of NLRP3 (39).…”

Macrophages in Renal Injury, Repair, Fibrosis Following Acute Kidney Injury and Targeted Therapy

“…The present understanding of macrophage functions in AKI derives mainly from studying various types of murine injury models, including nephrotoxin, ischemia reperfusion (IR), and rhabdomyolysis ( 15 ). Macrophages identify the primary damage signals through pattern recognition receptors (PRRs), a receptor of pathogen-associated molecular patterns (PAMPs), and recognize damage-associated molecular pattern (DAMPs) ( 16 ). NOD-like receptors (NLRs) and Toll-like receptors (TLRs) are the two main types of DAMPs.…”