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    • In light of this our finding that UBTD interacts with

    2020-05-29

    In light of this, our finding that UBTD1 interacts with ubiquitin conjugating enzymes is intriguing. Using two different screening approaches, we have demonstrated that UBTD1 interacts with the ubiquitin conjugating E2D family proteins. Using purified recombinant proteins and gel filtration chromatography we further show that the two proteins interact directly with each other in a complex. Mammals have around 30–40 different types of E2 enzymes that transfer activated ubiquitin from E1s to either E3s, or directly to target proteins in conjunction with E3s [27], [28]. We found that UBTD1 interacts exclusively with the UBE2D family of E2 enzymes for which several different E3 ligases and targets have been identified (e.g.: [29], [30]). The functional significance of UBTD1 forming a complex with UBE2D is still an open question. Some insights might be gained from a crystal structure of the UBTD1–UBE2D complex, which we are currently pursuing. For example, UBTD1 may bind to UBE2D via its UbL domain, thereby forming a possible ubiquitin-binding block. Alternatively, UBTD1 may bind via its UbL domain to UBE2D residues in the beta-sheet opposite to the active site where it has been shown that ubiquitin can bind non-covalently and enhance the processivity of ubiquitylation [31]. To study the latter possibility, we need to identify a physiological ubiquitylation target that is regulated by UBTD1 in combination with UBE2D. For instance, the UBE2D family of ligases had been shown to function in ubiquitylation of the tumor-suppressor protein p53 [32]. Some E2s have been shown to bind to co-factors that can alter the activity or subcellular localization of the recruited E2 [28]. One example is the CUE1 co-factor which recruits the cytoplasmic UBC7 (UBE2G2) E2 enzyme to the Artemether where it participates in the degradation of misfolded or regulated proteins in the ER [33]. It has been proposed that similar to ER-associated degradation (ERAD), mitochondrial proteins can also be degraded by the UPS in a process termed mitochondrial associated degradation (MAD). Others have demonstrated that UBTD2 is a mitochondrial protein and in preliminary studies we have made similar observations for UBTD1 (J.U. unpublished observations). In light of a possible mitochondrial localization, it may be relevant that UBTD1 also interacts with SHROOM3, an actin-associated protein and central regulator of cell shape during organogenesis. There are a number of reports demonstrating that the cytoskeleton is linked to mitochondria at the organelle, nucleoid, and mtDNA maintenance level [34], [35], [36]. Interestingly, UBTD1 also interacts with the nucleoporin/E3 ligase RANBP2, which is implicated in microtubule regulation [37] and mitochondrial transport [38], [39]. Further studies are clearly required to elucidate the in vivo function of UBTD1 and its functional role as a regulator of the UBE2D family of E2 ubiquitin conjugating enzymes.
    Acknowledgments This work was supported by the Knut and Alice Wallenberg Foundation (Grant number 2011/BAT) to M.F. and C.G., and by the European Research Council (Grant numbers 261248 and 268897) to M.F. and C.G.
    Introduction Cyclin E2 is a protein encoded by the human CCNE2 gene at 8q22.1 and is mostly regarded as being functionally redundant with cyclin E1.1, 2 Both cyclins E1 and E2 display high sequence similarity (69.3% in Homo sapiens), and important functional motifs are conserved. The latter include domains for Cdk (cyclin-dependent kinase) and Cdk inhibitor interaction, a nuclear localization sequence, and a centrosome localization sequence. The principal function of cyclin E2 is to help cells switch from G0/G1 to S phase by binding of CDK2 and phosphorylation of Rb protein.4, 5 Overexpression of cyclin E2 has been reported in many types of human cancers, including leukemia, breast cancer,7, 8 lung cancer, ovarian cancer, nasopharyngeal carcinoma, and bladder cancer.3, 12 In many types of cancer, overexpression of cyclin E2 correlates with tumor progression and mortality.3, 13 Additionally, dysregulation of cyclin E2 leads to chromosomal instability, suggesting that aberrant cyclin E2 expression contributes to tumorigenesis oncogenic transformation and cancer cell proliferation. The cell-cycle-dependent transcription of cyclin E2 is mediated by E2F transcription factors. In the study reported here, we found that the expression of cyclin E2 is regulated by miR-3687 in an indirect manner.