ReviewGene-to-screenThe E2 ubiquitin-conjugating enzyme UbcH5c: an emerging target in cancer and immune disorders
Introduction
Target proteins are linked with single or multiple ubiquitins, by which their stabilities, localizations, activities, and interactions with other proteins are changed. This PTM process of proteins, termed ‘ubiquitination’, is involved in diverse cellular processes, such as cell cycle progression, proliferation, apoptosis, differentiation, and gene expression and transcription 1, 2. The process of protein ubiquitination requires three types of enzyme: the ubiquitin-activating enzyme (E1), the ubiquitin-conjugating enzyme (E2), and the ubiquitin ligase (E3) 1, 2. E1 initially binds and transfers the ubiquitin to an E2 under an energy supply of ATP. Upon ubiquitin reception, E2 further transfers it to the target protein and forms the stable isopeptide linkages. E2 accomplishes this process by itself or via collaboration with an E3 [2].
Ubiquitin is a protein that comprises 76 amino acids, among which one methionine (Met) from the N terminus and seven lysines (Lys) can form polyubiquitin chains. The C terminus of ubiquitin can link to the target proteins for their ubiquitination [3]. There are six different topologies of ubiquitination, including monoubiquitination, multi-monoubiquitination, homogeneous ubiquitin chain, mixed ubiquitin chain, branched ubiquitin chain, and unanchored ubiquitin chain [4]. These topologies determine the ultimate fates of substrates. UbcH5c, also known as UBE2D3, engages in the protein ubiquitination and functions as an E2 [5]. UbcH5c forms ubiquitin chains on its substrates linked through K11, K48, and K63 [6]. As a ubiquitously expressed enzyme, UbcH5c exerts diverse catalytic actions, resulting in its multiple biological functions [4].
UbcH5c and another homologous E2, UbcH5b were discovered in 1995 [5]. These two E2s are similar in sequence with only four different amino acids. UbcH5c, UbcH5b, and two 88–90% identical E2s (i.e., UbcH5a and UbcH5d together have similar biological functions and constitute the UbcH5 protein family) [5]. UbcH5c and UbcH5b have similar activities in regulating the ubiquitination of their substrates, especially IκBα, p53, and p62 7, 8, 9. Knockdown or knockout of UbcH5b/c and co-inhibition of UbcH5b/c by small-molecule inhibitors blocked the ubiquitination and degradation of these client proteins 7, 8, 9, 10, 11. However, it is still unknown whether there is a significant difference between the functions of UbcH5c and UbcH5b because of the lack of methods that specifically inhibit UbcH5b or UbcH5c individually. Of note, UbcH5c shows the highest expression level among UbcH5 family members in all detected tissues and cell lines [5]. Nevertheless, the preference of the UbcH5 family might depend on the cellular context and the signaling pathways involved. In this review, we primarily focus on the biology and activity of UbcH5c and its signaling pathways, regulation, and relevance to cancer and immune disorders. The potential of UbcH5c as a cancer therapeutic target is also discussed.
Section snippets
Signaling pathways regulated by UbcH5c
As a ubiquitous enzyme, UbcH5c can catalyze the ubiquitination of a variety of proteins. UbcH5c has been frequently reported to be involved in four signaling pathways: NF-κB signaling, p53 signaling, p62-mediated autophagy, and DNA repair pathways. These signaling pathways have important roles in cancer and immune disorders.
UbcH5c and cancer
Directly or indirectly, UbcH5c shows inextricable links with cancer. The abnormal expression and activation of UbcH5c have been frequently observed in tumor tissues and cell lines from patients with cancer. Compared with the paired normal tissues, UbcH5c is overexpressed in thyroid oncocytic adenomas [48]. Similar studies and analyses have been applied to plasma samples from patients with colorectal cancer, 90% of whom have been found to have UbcH5c overexpression 49, 50. Moreover, compared
UbcH5c as a potential therapeutic target in cancer and immune disorders
UbcH5c is overexpressed in several types of human cancer and contributes to their initiation, progression, and metastasis by regulating various cancer-related signaling pathways. The role of NF-κB in cancer depends on the stages of the disease as well as the cellular context. In the specific types and stages of cancer, modulating NF-κB activity via UbcH5c could be a strategy for the prevention and treatment of these diseases. Considering the crucial role of p53 in cancer cell apoptosis,
Concluding remarks
Ubiquitination is a basic approach for cells to modify proteins and adjust the exertion of their biological activities. In recent years, ubiquitination has received increasing attention from researchers devoted to exploring effective cancer therapeutic strategies [108]. UbcH5c is a ubiquitous E2 with a crucial role in the ubiquitin-proteasome system. UbcH5c is overexpressed and activated in human cancers and immune disorders. UbcH5c inhibition by small molecules brings benefits to mice bearing
Acknowledgments
We thank the current and former members of our laboratories and collaborators for their contributions to the publications cited in this review article. The research field in UbcH5 is rapidly growing, and we apologize for not being able to cite all the recent publications, because of space limitations. This work was supported by National Natural Science Foundation of China (81903842, 81520108030, and 21472238), the National Key Research and Development Program of China (2017YFC1700200), Zhejiang
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