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  • In another study Nutlin a


    In another study, Nutlin-3a-mediated p53 activation induced strong negative impact on NF-κB signaling in LPS-stimulated neutrophils and macrophages [34]. Nutlin-3a limited cellular immune response to LPS, partly by attenuating DNA binding activity of NF-κB and impairing transcription of its target cytokine genes. At the same time p53-negative TAPI-1 demonstrated increased NF-κB DNA-binding activity and were characterized with elevated levels of cytokine release upon LPS stimulation compared to p53-positive cells. Later it was shown that Nutlin-3a-driven p53 activation also modulates dendritic cell-induced T cell proliferation [35], leads to transcriptional activation in human PBMCs and macrophages [36] and also suppresses M2 macrophage polarization by repressing transcription of c-MYC [37]. In addition, in T cells MDM2 is involved in negative regulation of TCR signaling by mediating NFAT pathway resulting in ubiquitination and proteasomal degradation of nuclear factor of activated T cells c2 (NFATc2), a crucial step in avoiding T cell-mediated immune overreaction in response to various stimuli. The study demonstrated that self-degrading auto-ubiquitination of MDM2 during T cell activation leads to nuclear accumulation of NFATc2 and followed by cytokine induction [38]. Such suicidal MDM2 auto-ubiquination can be blocked by USP15 deubiquitinase that prevents activation of NFATc2-mediated cytokine expression such as production of IFNγ by Th1 effector T cells.
    Cullin family Cullin RING E3 ligases (CRLs) constitute the largest family of E3 ligases with over 200 known members [39]. In certain cell types up to 20% of the proteasomal protein degradation is mediated by CRLs [40]. Assembly of the multi-subunit CRLs was originally reported for the archetypal Skp1–Cdc53–F-box Cdc4 (SCF) complex [41]. The CRL structure is based on modular organization of constituent subunits such as substrate receptors (F-box, SOCS-box, DCAF, BTB), adaptors (Skp1, ElonginB, ElonginC, DDB1, BTB), Cullin scaffolds (Cul1-Cul7, Cul9) and RING finger proteins (Rbx1 and Rbx2) [42,43]. The wide range of building blocks and their combinations enables formation of a multitude of functionally diverse E3 ligases [39,44,45]. CRLs and their constituent Cullin proteins are implicated in various types of immune cell functions and signaling outcomes. For example, Cul4A affects granulocyte differentiation and cell cycle [46]. On the other hand, its close homolog Cul4B sustains the levels of macrophage secreted cytokine tumor necrosis factor alpha (TNFα) [47] and also negatively regulates LPS-induced peritonitis [48]. FBXO1, an F-box protein family member, is a substrate-recognition subunit of the SCF-type E3 ubiquitin ligase. A recent genomic study revealed that expression of CCNF gene encoding FBXO1 can lead to aberrant ubiquitination and affect the mechanisms of neuronal degeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [49]. In another example negative regulation of Treg functions was demonstrated by SCF with F-box protein Skp2 as substrate recognition domain (SCFSkp2) [50]. Here, SCFSkp2 was found to be involved in regulation of Treg cell cycle control and death. Overexpression of SCFSkp2 suppressed Treg functions via induced loss of Foxp3, an essential transcriptional regulator crucial for immune system homeostasis. On the contrary, SCFSkp2 downregulation resulted in transformation of auto-reactive pathogenic T cells into Foxp3 expressing Tregs. Von Hippel-Lindau disease tumor suppressor (VHL) is a well-described substrate recognition subunit in CRL2VHL E3 ubiquitin ligase that mediates proteasomal degradation of hypoxia-inducible factor 1 alpha (HIF-1α) as its primary substrate. VHL-mediated alteration of HIF-1α levels was demonstrated to be essential for Treg stability and suppressive capacity [51]. HIF-1α binds to Ifng gene promoter and enhances transcription of this gene, therefore directly affecting levels of IFNγ produced by Treg cells. Animal studies demonstrated that VHL-deficient Tregs produce excessive amount of IFNγ that leads to increased inflammation, whereas HIF-1α knockdown or knockout balances excessive IFNγ production in these cells.