Mechanism and disease association of E2-conjugating enzymes: lessons from UBE2T and UBE2L3

Abstract

Ubiquitin signalling is a fundamental eukaryotic regulatory system, controlling diverse cellular functions. A cascade of E1, E2, and E3 enzymes is required for assembly of distinct signals, whereas an array of deubiquitinases and ubiquitin-binding modules edit, remove, and translate the signals. In the centre of this cascade sits the E2-conjugating enzyme, relaying activated ubiquitin from the E1 activating enzyme to the substrate, usually via an E3 ubiquitin ligase. Many disease states are associated with dysfunction of ubiquitin signalling, with the E3s being a particular focus. However, recent evidence demonstrates that mutations or impairment of the E2s can lead to severe disease states, including chromosome instability syndromes, cancer predisposition, and immunological disorders. Given their relevance to diseases, E2s may represent an important class of therapeutic targets. In the present study, we review the current understanding of the mechanism of this important family of enzymes, and the role of selected E2s in disease.

Increased expression of UBE2T predicting poor survival of ovarian cancer: based on comprehensive analysis of UBE2s, clinical samples and the GEO database

“…UBE2T, also known as FANCT or HSPC150, is essential for FANCD2 monoubiquitination. It combines with a speci c ubiquitin E3 ligase to degrade speci c substrates, contributing to DNA repair in the Fanconi anemia pathway and playing a key role in cell proliferation and the maintenance of genomic stability [50]. Recently, UBE2T expression has been reported to be signi cantly upregulated in hepatocellular carcinoma [10], renal cell carcinoma [51], prostate cancer [15], breast cancer, and lung adenocarcinoma [52], and its high expression is associated with poor prognosis in patients.…”

Structural basis of generic versus specific E2–RING E3 interactions in protein ubiquitination

“…The Fanconi anemia pathway mediates DNA interstrand crosslink repair, where site-specific monoubiqutination of FANCD2 acts as the key signaling event that triggers recruitment of the required downstream DNA repair factors. 28 The RING E3 ligase FANCL interacts with UBE2T to mediate FANCD2 monoubiqutination. 39 With the UBE2T-FANCL binding affinity being in the sub-μM range, FANCL exclusively select UBE2T from a pool of E2s.…”

“…As a result, a given E3 has the potential to recognize numerous E2~Ub conjugates, and vice versa . At the same time, with the type of Ub signal generated specified by the E2, E3s have to be able to select the right E2 to generate the appropriate Ub signal on the appropriate target protein . The question of how E3s evolved to discriminate between 38 structurally similar E2s has therefore been an area of intensive research, and with over 50 E2–E3 complex structures deposited in the Protein Data Bank (PDB) to date, the answer is beginning to emerge.…”

“…23,24 At the same time, with the type of Ub signal generated specified by the E2, [25][26][27] E3s have to be able to select the right E2 to generate the appropriate Ub signal on the appropriate target protein. 10,28,29 The question of how E3s evolved to discriminate between 38 structurally similar E2s has therefore been an area of intensive research, and with over 50 E2-E3 complex structures deposited in the Protein Data Bank (PDB) to date, the answer is beginning to emerge. Aiming to avoid redundancy with recent, extensive reviews on HECT-and RBR-family E3s, 19,22 the focus will be on recent findings in E2-RING interactions.…”

UBE2T is upregulated, predicts poor prognosis, and promotes cell proliferation and invasion via inhibiting autophagy in ovarian cancer

“…Ubiquitin-conjugating enzyme E2T (UBE2T) is rstly identi ed in the study of Fanconi anaemia syndrome (FA) and plays vital roles in the development of FA via catalyzing the mono-ubiquitination of FANCD2 and FANCI. Accordingly, high mutation rate of UBE2T is observed in patients with FA [8]. Recently, the roles of UBE2T have been revealed in cancers.…”