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    • Multi subunit RING type E ligases are exemplified

    2019-10-07

    Multi-subunit RING-type E3 ligases are exemplified by the CULLIN-RING-ligase (CRL) and the anaphase-promoting complex/cyclosome (APC/C) [19]. CRLs constitute the biggest family of other multi-component E3 ligases. These consist of a cullin scaffold protein (CULLIN 1, 2, 3, 4A, 4B, 5, 7), a substrate receptor, an adaptor, and a RING domain protein for E2 enzyme recruitment. A large body of evidence suggests that CRLs share a similar molecular architecture, where substrates are recruited at the N-terminal regions of the cullins, which comprise of an adaptor protein and a substrate receptor [24], [25]. For the well-characterized example of CULLIN1, the adaptor protein is SKP1, which recruits numerous substrate receptors (i.e., the F-box proteins). SKP1 can interact with both CULLIN1 and CULLIN7, while CULLIN2 and CULLIN5 utilize the elongin B/C adaptor 5-Methyl-CTP to recruit the substrate receptors; a family of proteins, which is named suppressor of cytokine signaling/elongin BC (SOCS/BC)-box-protein. CULLIN3 is unique; it utilizes a BTB domain-containing protein that can function both as an adaptor and a substrate receptor. CULLIN4A uses the adaptor protein DNA damage-binding protein-1 (DDB1), which in turns binds to substrate receptor proteins such as the DDB1 and CUL4 associated factors (DCAFs). The biological function of the cullins is involved in various cellular processes; these include cell cycle, signaling transduction, cell proliferation and survival, and DNA damage response [24]. The third class of E3 ligases is that of the RBR E3 ligases, which consists of a RING1, an intermediate RING (IBR), and a RING2 domain (Fig. 1). These ligases use a unique mode of catalyzing the ubiquitin transfer by combining both the RING-type and HECT-type E3 ligase mechanisms. Similar to classical RING-type ligases, these recognize the E2 conjugated ubiquitin by the RING1 domain and form a HECT-like intermediate by accepting the ubiquitin to the cysteine of the RING2 domain. The ubiquitin is finally transferred to the substrate by the RING2 [26].
    Ubiquitin ligases in B-cell lymphoid malignancies Increasing evidence supports that the B-cell lymphoid malignancies develop from various stages of B-cells, hijacking the mechanisms that drive B-cell differentiation and activation [27]. For instance, mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) originate from the pre-germinal center (GC) mature B-cells, while most of the non-Hodgkin’s lymphomas and multiple myelomas (MMs) originate from the GC B-cells or B-cells that have gone through a germinal center reaction. Each of these B-cell lymphoid malignancies features different genomic alterations, including chromosomal translocations, amplifications, frameshift deletions, and mutations, to ultimately activate the oncogenic signaling programs that promote growth and survival [28]. Sequencing efforts have identified many E3 ubiquitin ligases that are mutated, amplified, or deleted in B-cell lymphoid malignancies, functioning either as a tumor suppressor or oncogene [29]. Importantly, the success of a proteasome inhibitor (bortezomib), in both MM and MCL, has further inspired the investigation of the biological significance of protein ubiquitylation and degradation in B-cell cancers [30], [31], [32]. Thus, the understanding of how the ubiquitylation of protein is achieved, and of the downstream molecular events, is critical for the development of therapeutic approaches. Targeting specific E3 ubiquitin ligases has garnered attention as it confers a selective advantage over a proteasome inhibitor by preventing any unwanted toxic effects on intra-cellular proteins. In this review, we will discuss a wide spectrum of E3 ligases that have been implicated in the pathogenesis of B-cell malignancies (Fig. 1 and Table 1).
    Concluding remarks BCL6, BCL2, and c-MYC are dominant oncogenes deregulated by chromosomal rearrangement and missense mutations in lymphoma arising from germinal center B-cells such as BL, FL, or GCB-DLBCL. Protein ubiquitylation adds another layer to the biology of GC lymphoma as discussed in this review. Specifically, BCL6 is overexpressed and stabilized by inactivation of FBXO11 and Pellino1-induced Lys63-polyubiquitylation. MYC is up-regulated by Smurf2-mediated activation of YY1 or by mutations of its FBXW7 degron. In addition, the substrate interaction domain of FBXO10 is disrupted to impair the proteasomal degradation of BCL2. Thus, different lymphoma subtypes are characterized by inappropriate turnover of key cellular players for that particular stage of B-cell differentiation (Fig. 2).