Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Feb 21:13:793610.
doi: 10.3389/fimmu.2022.793610. eCollection 2022.

Mechanism and Disease Association With a Ubiquitin Conjugating E2 Enzyme: UBE2L3

Xiaoxia Zhang  1   2 , Chengdong Huo  1   2 , Yating Liu  2 , Ruiliang Su  2 , Yang Zhao  2 , Yumin Li  2
Affiliations
Review

Mechanism and Disease Association With a Ubiquitin Conjugating E2 Enzyme: UBE2L3

Xiaoxia Zhang et al. Front Immunol. .

Abstract

Ubiquitin conjugating enzyme E2 is an important component of the post-translational protein ubiquitination pathway, which mediates the transfer of activated ubiquitin to substrate proteins. UBE2L3, also called UBcH7, is one of many E2 ubiquitin conjugating enzymes that participate in the ubiquitination of many substrate proteins and regulate many signaling pathways, such as the NF-κB, GSK3β/p65, and DSB repair pathways. Studies on UBE2L3 have found that it has an abnormal expression in many diseases, mainly immune diseases, tumors and Parkinson's disease. It can also promote the occurrence and development of these diseases. Resultantly, UBE2L3 may become an important target for some diseases. Herein, we review the structure of UBE2L3, and its mechanism in diseases, as well as diseases related to UBE2L3 and discuss the related challenges.

Keywords: NF-κB; Parkinson’s disease; UBE2L3; Ubiquitination; cancer; immune diseases; p53; p62.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The process of ubiquitination. Ub is activated by E1 through an ATP-dependent step. The activated Ub attaches to the E2. The binding of Ub to target proteins can be catalyzed by HECT and RBR-type E3 ligases, or RING domain E3 ligases. This acts as a bridge between the activated E2 and the substrate indicating that the ubiquitin signals form polyubiquitin chains. Finally, the substrate is degraded by the 26S proteasome.
Figure 2
Figure 2
The structures of HECT-type (A) and RBR family (B) E3 ubiquitin-protein ligases in complexes with UBE2L3. (A) The catalytic HECT structure of E6AP is double-lobed (yellow, blue), and there is a large catalytic crack at the junction of the two lobed structures. The crack contains conserved residues(green) formed by mutated interference with the ubiquitin-thioester bond. (B) Ring-in-between-ring (RBR) ubiquitin E3 ligase(blue) binds to Ub(red)-UBE2L3(green) through RING/HECT hybridization mechanism.
Figure 3
Figure 3
UBE2L3 binding with different E3 ubiquitin ligases acts on NF-κB signaling pathway. Upon the stimulation of IL-1R, TAX interacts with UBE2L3 to synthesize the heterotypic chains, resulting in IκB phosphorylation, and the degradation and activation of NF-κB. In the TNFR pathway, UBE2L3 interacts with LUBAC to synthesize first, a linear ubiquitin chain, then there is a linear ubiquitination of NEMO and a phosphorylation of IKKβ, ultimately leading to the activation of NF-κB. While OspG can interact with UBE2L3-Ub conjugates to improve the kinase activity of OspG, which inhibit the activation of NF-κB.
Figure 4
Figure 4
UBE2L3 acts on the GSK3β/p65 signaling pathway. UBE2L3 participates in the ubiquitination of GSK3β and promotes the degradation of GSK3β, leading to a decrease on the expression of p65, thereby inhibiting apoptosis.
Figure 5
Figure 5
UBE2L3 acts on DSB repair and cell survival.
Figure 6
Figure 6
This model describes the interaction of the p62 signaling pathway with the UPS to activate autophagy.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Glickman MH, Ciechanover A. The Ubiquitin-Proteasome Proteolytic Pathway: Destruction for the Sake of Construction. Physiol Rev (2002) 82(2):373–428. doi: 10.1152/physrev.00027.2001 - DOI - PubMed
    1. Popovic D, Vucic D, Dikic I. Ubiquitination in Disease Pathogenesis and Treatment. Nat Med (2014) 20(11):1242–53. doi: 10.1038/nm.3739 - DOI - PubMed
    1. Heaton SM, Borg NA, Dixit VM. Ubiquitin in the Activation and Attenuation of Innate Antiviral Immunity. J Exp Med (2015) 213(1):1–13. doi: 10.1084/jem.20151531 - DOI - PMC - PubMed
    1. Gilberto S, Peter M. Dynamic Ubiquitin Signaling in Cell Cycle Regulation. J Cell Biol (2017) 216(8):2259–71. doi: 10.1083/jcb.201703170 - DOI - PMC - PubMed
    1. Pickart CM. Mechanisms Underlying Ubiquitination. Annu Rev Biochem (2001) 70(1):503–33. doi: 10.1146/annurev.biochem.70.1.503 - DOI - PubMed

Publication types

MeSH terms