Disease relevance of UBD

• This study revealed that FAT10 expression is induced after infection of RTEC by HIV-1 and that expression of FAT10 induces apoptosis in RTEC in vitro [1].

High impact information on UBD

• The other UBD, RUZ (Rabex-5 ubiquitin binding zinc finger) binds to a surface of Ub centered on Asp58(Ub) and distinct from the "canonical" Ile44(Ub)-based surface [2].
• Here, I give an overview of important ubiquitin-related protein motifs, including the UBA, UIM, UBD and UBX domains, and propose a model for the role of subclasses of UBA-domain-containing proteins in ubiquitin-mediated proteolysis [3].
• Although the interaction of UBA2 with Lys48-linked diubiquitin involves the same hydrophobic surface on each ubiquitin unit as that utilized in monoubiquitin:UBA complexes, our results show how the "closed" conformation of Lys48-linked diubiquitin is crucial for high-affinity binding [4].
• Thus, FAT10 may modulate cell growth during B cell or dendritic cell development and activation [5].
• In various cell lines, FAT10 expression was shown to be induced by gamma interferon or by tumor necrosis factor alpha [6].

Biological context of UBD

• In conclusion, we demonstrated upregulation of FAT10 expression in various gastrointestinal and gynecological cancers [7].
• FAT10 (diubiquitin) belongs to this family of proteins, comprising two ubiquitin-like moieties fused in tandem, and has been implicated to be involved in the maintenance of spindle integrity during mitosis [7].
• CONCLUSION: FAT10 expression is regulated during cell-cycle [8].
• High FAT10 expression was found to lead to increased chromosome instability via the reduction in the kinetochore localization of MAD2 during the prometaphase stage of the cell-cycle [8].
• Ten days later, action potentials of single-unit pelvic C-fiber afferents with receptive fields in the bladder were recorded under urethane anesthesia during graded bladder distensions (UBD) or intravesical capsaicin (vCP) administration [9].

Anatomical context of UBD

• FAT10 expression was also found to be highly upregulated in other cancers of the gastrointestinal tract and female reproductive system [7].
• FAT10 mRNA is expressed constitutively in some lymphoblastoid lines and dendritic cells and in certain other cells after gamma-interferon induction [5].
• FAT10-green fluorescent protein fusion proteins were not cleaved but entirely degraded, suggesting that FAT10-specific deconjugating enzymes were not present in the analyzed cell lines [10].
• UBD, a downstream element of FOXP3, allows the identification of LGALS3, a new marker of human regulatory T cells [11].
• Here, we report the identification of the ubiquitin-like gene UBD as a downstream element of FOXP3 in human activated regulatory CD4(+)CD25(hi) T cells (T(reg)) [11].

Associations of UBD with chemical compounds

• FAT10 bears a diglycine motif at its C terminus that can form isopeptide bonds to so far unidentified target proteins [12].
• A yeast two-hybrid screen identified NEDD8 ultimate buster-1L (NUB1L) as a non-covalent binding partner of FAT10, and this interaction was confirmed by coimmunoprecipitation and glutathione S-transferase pull-down experiments [12].
• In the presence of ionomycin, overexpression of UBD in T(h) cells leads to the induction of IL1R2 that resemble FOXP3-transduced T(h) cells and naturally derived T(reg) cells [11].
• More nocodazole-treated FAT10-overexpressing cells escape mitotic controls and are multinucleate compared with parental cells [13].

Physical interactions of UBD

• NEDD8 ultimate buster-1L interacts with the ubiquitin-like protein FAT10 and accelerates its degradation [12].
• However, the interaction is dissimilar to the molecular models proposed for the hHR23A UBA domains bound to either monoubiquitin or Lys48-linked diubiquitin [14].

Enzymatic interactions of UBD

• SARS CoV-PLpro hydrolyzed both diubiquitin and ubiquitin-7-amino-4-methylcoumarin (AMC) substrates, and hydrolysis of ubiquitin-AMC is approximately 180-fold more efficient than hydrolysis of a peptide substrate that mimics the PLpro replicase recognition sequence [15].

Regulatory relationships of UBD

• Expression of the FAT10 gene is highly upregulated in hepatocellular carcinoma and other gastrointestinal and gynecological cancers [7].
• RESULTS: Here, we report that FAT10 expression is regulated at the protein and transcript level during cell-cycle with highest expression observed during the S-phase of the cell-cycle [8].

Other interactions of UBD

• The coexpression of NUB1L enhanced the degradation rate of FAT10 8-fold, whereas NEDD8 degradation was only accelerated 2-fold [12].
• Because NUB1 was shown to bind to the proteasome subunit RPN10 in vitro and to be contained in 26 S proteasome preparations, it may function as a linker that targets FAT10 for degradation by the proteasome [12].
• Rather, FAT10 may modulate tumorigenesis through its reported interaction with the MAD2 spindle-assembly checkpoint protein [7].
• This purification scheme can be applied to other small ubiquitin-like proteins, especially those with limited protein targets such as the SUMOs (1, 2, and 3), Isg15, or FAT10 [16].
• We have recently demonstrated the upregulation of FAT10 gene expression in 90% of hepatocellular carcinoma patients [17].

Analytical, diagnostic and therapeutic context of UBD

• Northern blot analyses revealed upregulation of FAT10 expression in the tumors of 90% of HCC patients [7].
• However, flow cytometry analysis demonstrated that the lymphocytes of FAT10 knockout mice were, on average, more prone to spontaneous apoptotic death [6].
• Real-time PCR and in situ hybridization analyses identified three molecules, ubiquitin D (Ub-D), tumor necrosis factor receptor superfamily 12a (TNFRsf12a), and transmembrane 4 superfamily 4 (Tm4sf4), which were predominantly distributed throughout FAE, but were expressed little, if at all, in IECs [18].

References