The E2 ubiquitin-conjugating enzyme UbcH5c: an emerging target in cancer and immune disorders

Highlights

• UbcH5c is an important ubiquitin-conjugating enzyme in the UbcH5 family.

• UbcH5c is aberrantly expressed in human cancer and immune disorders.

• UbcH5c regulates the p53, NF-κB, DNA repair, and p62 signaling pathways.

• Targeting UbcH5c is a potential strategy for treating cancer and immune diseases.

Ubiquitination is a crucial post-translational modification (PTM) of proteins and regulates their stabilities and activities, thereby modulating multiple signaling pathways. UbcH5c, a member of the UbcH5 ubiquitin-conjugating enzyme (E2) protein family, engages in the ubiquitination of dozens of proteins and regulates nuclear factor kappa-B (NF-κB), p53 tumor suppressor, and several other essential signaling pathways. UbcH5c has been reported to be abnormally expressed in human cancer and immune disorders and is involved in the initiation and progression of these diseases. In this review, we mainly focus on UbcH5c structure, activity, signaling pathways, and its relevance to cancer and immune disorders. We end by integrating all known factors relating to UbcH5c inhibition as a potential cancer therapy method, and discuss associated challenges.

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.