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  • Here we discuss implications of

    2019-10-08

    Here, we discuss implications of several major families of RING-type E3 ubiquitin ligases (MDM, Cullin, GRAIL, TRAF, TRIM) as targets in inflammation and immunity, and provide insights into potential small molecule interventions to mediate the cellular responses (summarized in Table 1). We briefly cover the role of RING-type E3 ubiquitin ligases in substrate protein stability and trafficking, T cell signaling and cytokine productions upon activating stimulus.
    MDM family Murine double minute 2 (MDM2) protein is mainly known as a negative regulator of primary oncosuppressor and transcription factor p53. These two proteins are linked in tightly regulated negative feedback loop whereby MDM2 ubiquitinates p53 resulting in its proteasomal degradation [21]. The importance of p53 activation in immune response and inflammation has been implicated a lot in recent years revealing that p53 is responsible for transactivating genes involved in pathogen recognition, cytokine production, immune checkpoint regulation and broadly in the maintenance of immune homeostasis [[22], [23], [24]]. MDM2 also regulates nuclear factor–kappa-light-enhancer of activated (+)-MK 801 mass (NF-κB), a primary transcription factor that serves as master regulator of cell signaling by coordinating immune and inflammatory responses [25]. In that capacity MDM2 functions as non-redundant co-factor for NF-κB signaling by facilitating binding of NF-κB to promoter regions of (+)-MK 801 mass its target genes [26]. Importantly, MDM2 is transcriptional target for both p53 and NF-κB, therefore MDM2–p53–NFk-B axis is believed to function as potential link between inflammation and tumorigenesis [27]. Despite normally having antagonistic roles in cancer, p53 and NF-κB demonstrate concerted signaling in inflammation, i.e. they co-regulate transcription of inflammation-associated genes in human macrophages and T cells [28]. In that way, MDM2 promotes mostly pro-survival NF-κB signaling and blocks mostly pro-apoptotic p53 signaling, thereby small molecule MDM2 inhibitors like Nutlin-3a act as NF-κB antagonists and p53 agonists. In response to Nutlin-3a both p53 and NF-κB induce pro-inflammatory responses by binding to promoter regions of cytokine genes and promoting production of cytokines, i.e. IL-6 and IL-8. MDM2 represents a novel and highly promising target for therapeutic intervention in multiple inflammatory autoimmune diseases, including MS, SLE, lupus nephritis and primary Sjogren\'s syndrome [29]. MDM2 was previously reported to be upregulated in SLE animal models and inhibition of this E3 enzyme is considered as a promising approach to suppress inflammation. Nutlin-3a was demonstrated to reduce systemic inflammation in SLE and lupus nephritis by blocking formation of immune complex and suppressing abnormal expansion of all T cell subsets linked to systemic inflammation [30]. MDM2 suppression substantially reduced lymph proliferation through depletion of auto-reactive T cells and plasma cells, and also inhibited production of auto-antibodies. Animal model experiments revealed that MDM2 upregulation induced expansion of plasma cells and double negative CD3+CD4−CD8– T cells that promote production of auto-antibodies. These results support the opinion that MDM2 is a valuable therapeutic target for treatment of SLE, lupus nephritis and, potentially, other autoimmune diseases associated with polyclonal antibody production. In agreement with this, substantially higher levels of anti-MDM2 auto-antibodies were detected in SLE and primary Sjogren\'s syndrome patients compared to healthy humans suggesting potential role of MDM2 as serological marker in pathogenesis of these diseases [31,32]. The involvement of MDM2 in mechanisms underlying development of inflammatory autoimmune diseases is additionally supported by recent data showing that MDM2 promotes rheumatoid arthritis [33]. Here, collagen-induced arthritis mouse model was used to demonstrate that high MDM2 levels correlated with disease severity and stimulates release of pro-inflammatory cytokines through activation of NF-κB and MAPK signaling pathways. Whereas, inhibition of MDM2 by Nutlin-3a reduced inflammation and suppressed propagation of immune response.