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

Zhang, Xiaoxia; Huo, Cheng-Dong; Liu, Yating; Su, Ruiliang; Zhao, Yang; Li, Yumin

doi:10.3389/fimmu.2022.793610

Cited by 8 publications

(4 citation statements)

References 188 publications

(253 reference statements)

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“…UBE2L3 is known to promote cell growth in non-small cell lung cancer (NSCLC) [77] . Also, its interaction with GSK3β stimulates the development of certain tumors including colorectal cancer [78] . Similarly, CYCS known to to regulate tumor growth in renal cell carcinoma [79] .…”

Section: Discussionmentioning

confidence: 99%

Virus-host interaction analysis in colorectal cancer identifies core virus network signature and small molecules

AVS

Sinha²,

Donakonda³

2022

Computational and Structural Biotechnology Journal

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Section: Discussionmentioning

confidence: 99%

Virus-host interaction analysis in colorectal cancer identifies core virus network signature and small molecules

AVS

Sinha²,

Donakonda³

2022

Computational and Structural Biotechnology Journal

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“…Interestingly, given that single nucleotide polymorphisms (SNPs) located near or within m 6 A motifs have been proposed as possible contributors to disease, a recent study identified five candidate genes corresponding to two of the major IBD subtypes: ubiquitin-conjugating enzyme E2L3 (UBE2L3) and solute carrier family 22 member 4 (SLC22A4) for Crohn's disease and transcription factor 19 (TCF19), chromosome 6 open reading frame 47 (C6orf47), and small nuclear RNA-activating complex polypeptide 4 (SNAPC4) for ulcerative colitis [64]. UBE2L3 functions in the ubiquitination of tumor protein P53 (TP53), the proto-oncogene c-FOS, and the NF-kappa-B (NF-kB) precursor p105 [65]. SLC22A4 functions as a polyspecific organic cation transporter, which is critical for elimination of many endogenous small organic cations and a wide array of drugs and environmental toxins [66], while SNAPC4 is associated with spondylitis [67].…”

Section: Modification Of Mrna In Ibdmentioning

confidence: 99%

RNA Modification in Inflammatory Bowel Diseases

et al. 2022

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Inflammatory bowel disease (IBD) is a chronic inflammatory disorder characterized by damage to the intestinal mucosa, which is caused by a combination of factors. These include genetic and epigenetic alterations, environmental influence, microorganism interactions, and immune conditions. Some populations with IBD show a cancer-prone phenotype. Recent studies have provided insight into the involvement of RNA modifications in the specific pathogenesis of IBD through regulation of RNA biology in epithelial and immune cells. Studies of several RNA modification-targeting reagents have shown preferable outcomes in patients with colitis. Here, we note a new awareness of RNA modification in the targeting of IBD and related diseases, which will contribute to early diagnosis, disease monitoring, and possible control by innovative therapeutic approaches.

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“…The SCF ubiquitin ligase complex ubiquitinates many cell cycle regulatory proteins, such as E2F1, p27, origin recognition complex subunit 1, and cyclin D1 ( 18 – 21 ). UBE2L3 interacts with various E3 ligases containing HECT (homologous of E6AP C-terminus) or RING (Really Interesting New Gene) finger domains ( 22 , 23 ). Following SCF-mediated ubiquitination, E7 is degraded via the 26S proteasome ( 17 , 24 ).…”

Section: Introductionmentioning

confidence: 99%

The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer

Khalil,

Yang,

et al. 2024

J Virol

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The human papillomavirus (HPV) oncoprotein E7 is a relatively short-lived protein required for HPV-driven cancer development and maintenance. E7 is degraded through ubiquitination mediated by cullin 1 (CUL1) and the ubiquitin-conjugating enzyme E2 L3 (UBE2L3). However, E7 proteins are maintained at high levels in most HPV-positive cancer cells. A previous proteomics study has shown that UBE2L3 and CUL1 protein levels are increased by the knockdown of the E3 ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8). We have recently demonstrated that HPV16 upregulates MARCHF8 expression in HPV-positive keratinocytes and head and neck cancer (HPV+ HNC) cells. Here, we report that MARCHF8 stabilizes the HPV16 E7 protein by degrading the components of the S-phase kinase-associated protein 1-CUL1-F-box ubiquitin ligase complex in HPV+ HNC cells. We found that MARCHF8 knockdown in HPV+ HNC cells drastically decreases the HPV16 E7 protein level while increasing the CUL1 and UBE2L3 protein levels. We further revealed that the MARCHF8 protein binds to and ubiquitinates CUL1 and UBE2L3 proteins and that MARCHF8 knockdown enhances the ubiquitination of the HPV16 E7 protein. Conversely, the overexpression of CUL1 and UBE2L3 in HPV+ HNC cells decreases HPV16 E7 protein levels and suppresses tumor growth in vivo . Our findings suggest that HPV-induced MARCHF8 prevents the degradation of the HPV16 E7 protein in HPV+ HNC cells by ubiquitinating and degrading CUL1 and UBE2L3 proteins. IMPORTANCE Since human papillomavirus (HPV) oncoprotein E7 is essential for virus replication; HPV has to maintain high levels of E7 expression in HPV-infected cells. However, HPV E7 can be efficiently ubiquitinated by a ubiquitin ligase and degraded by proteasomes in the host cell. Mechanistically, the E3 ubiquitin ligase complex cullin 1 (CUL1) and ubiquitin-conjugating enzyme E2 L3 (UBE2L3) components play an essential role in E7 ubiquitination and degradation. Here, we show that the membrane ubiquitin ligase membrane-associated ring-CH-type finger 8 (MARCHF8) induced by HPV16 E6 stabilizes the E7 protein by degrading CUL1 and UBE2L3 and blocking E7 degradation through proteasomes. MARCHF8 knockout restores CUL1 and UBE2L3 expression, decreasing E7 protein levels and inhibiting the proliferation of HPV-positive cancer cells. Additionally, overexpression of CUL1 or UBE2L3 decreases E7 protein levels and suppresses in vivo tumor growth. Our results suggest that HPV16 maintains high E7 protein levels in the host cell by inducing MARCHF8, which may be critical for cell proliferation and tumorigenesis.

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

Cited by 8 publications

References 188 publications

Virus-host interaction analysis in colorectal cancer identifies core virus network signature and small molecules

Virus-host interaction analysis in colorectal cancer identifies core virus network signature and small molecules

RNA Modification in Inflammatory Bowel Diseases

The membrane-associated ubiquitin ligase MARCHF8 stabilizes the human papillomavirus oncoprotein E7 by degrading CUL1 and UBE2L3 in head and neck cancer

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