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.

Keywords: DUB inhibitors; E3 ligases; NOD-like receptor; RIG-I-like receptor; Toll-like receptor; innate immunity; macrophages.

Figure 1

Regulation of the antiviral immune responses by ubiquitination in macrophages. After recognition of cytoplasmic viral RNA species, TLRs and RLRs signals through the downstream adaptors MyD88/TRIF and MAVS, respectively. The MyD88/TRIF adaptor then propagate TLR signal to TRAF6 and NF-κB (p50 and p65) activation. K63-linked polyubiquitination recruits the TAK1/TAB1 complex, which leads to phosphorylation of IκBa. Degradation of IκBα by phosphorylation releases the p50 and P65, leading to induction of proinflammatory cytokines. RLRs signals via the mitochondrial adaptor MAVS are strictly regulated by K63- and K48-linked polyubiquitination. RIG-I is activated by K63-linked polyubiquitination mediated by TRIM25, which is inhibited by USP21. On the other hands, RNF125-mediated K48-linked polyubiquitination of RIG-I induces its degradation by the proteasome, which can be inhibited by USP4 and USP17. The cytoplasmic viral DNA can be recognized by cGAS, which activates STING via synthesizing the second messenger (c-di-GMP and c-di-AMP) and K48-lined ubiquitination. Activated STING facilitates type I IFN gene expression. Dark purple circles indicated K48-linked ubiquitination and light purple circles indicate K63-linked ubiquitination. The details of how specific DUBs regulates the activities of the TLRs and RLRs signaling molecules are described in the text.

Figure 2

Schematic diagram of the mechanism of NLRP3 inflammasome activation by ubiquitination in macrophages. Inflammasome requires a priming signal, such as LPS, that activates the NF-κB subunits (p50 and p65), leading to upregulation of pro-IL-1β/IL-18 and NLRP3 genes in macrophages. Activation signals, such as ATP and bacterial toxins, increase potassium influx, which recruits ASC and Caspase-1 to assemble the active NLRP3 inflammasome complex. Caspase-1 generated by active NLRP3 inflammasome cleaves and secretes proinflammatory cytokines such as IL-1β and IL-18. Dark purple circles indicated K48-linked ubiquitination and light purple circles indicate K63-linked ubiquitination. The details of how specific DUBs and DUB inhibitors regulate the activities of the NLRP3 inflammasome signaling molecules are described in the text.