The E3 ubiquitin ligase Cul4b promotes CD4+ T cell expansion by aiding the repair of damaged DNA

Dar, Asif Amin; Sawada, Keisuke; Dybas, Joseph M.; Moser, Emily K.; Lewis, Emma L.; Park, Eddie; Fazelinia, Hossein; Spruce, Lynn A.; Ding, Hua; Seeholzer, Steven H.; Oliver, Paula

doi:10.1371/journal.pbio.3001041

Cited by 17 publications

(17 citation statements)

References 96 publications

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“…These findings are consistent with a very recent report that ablation of Cul4b in mature T cells resulted in impaired survival and proliferation accompanied by accumulation of DNA damage upon T-cell stimulation (39). This recent study further demonstrated that Cul4-Ddb1-DCAF1 E3 ligase complex associated with a DNA damage repair complex including SMC1A and promoted phosphorylation of Smc1a to aid in DNA damage repair (39). As Ddb1 is crucial for activity of Cul4-Ddb1-DCAFs E3 ligase complex, deletion of Ddb1 in effector CD4 + T cells could result in augmented protein levels of substrates involved in regulation of cell cycle, such as Cdt1 (18,19), p21 (20,21), and Cyclin D (40)(41)(42).…”

Section: Discussionsupporting

confidence: 93%

“…Therefore, mutations in NER components such as Ddb1 deletion cause aberrant accumulation of DNA damage that lead to activation of the ATM/ATR-Chk1 and p53 pathway and consequently promotes cell cycle arrest and cell death. These findings are consistent with a very recent report that ablation of Cul4b in mature T cells resulted in impaired survival and proliferation accompanied by accumulation of DNA damage upon T-cell stimulation ( 39 ). This recent study further demonstrated that Cul4-Ddb1-DCAF1 E3 ligase complex associated with a DNA damage repair complex including SMC1A and promoted phosphorylation of Smc1a to aid in DNA damage repair ( 39 ).…”

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

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Ddb1 Is Essential for the Expansion of CD4+ Helper T Cells by Regulating Cell Cycle Progression and Cell Death

Yang

Chen

et al. 2021

Front. Immunol.

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Follicular helper T (TFH) cells are specialized CD4+ helper T cells that provide help to B cells in humoral immunity. However, the molecular mechanism underlying generation of TFH cells is incompletely understood. Here, we reported that Damage-specific DNA binding protein 1 (Ddb1) was required for expansion of CD4+ helper T cells including TFH and Th1 cells, germinal center response, and antibody response to acute viral infection. Ddb1 deficiency in activated CD4+ T cells resulted in cell cycle arrest at G2-M phase and increased cell death, due to accumulation of DNA damage and hyperactivation of ATM/ATR-Chk1 signaling. Moreover, mice with deletion of both Cul4a and Cul4b in activated CD4+ T cells phenocopied Ddb1-deficient mice, suggesting that E3 ligase-dependent function of Ddb1 was crucial for genome maintenance and helper T-cell generation. Therefore, our results indicate that Ddb1 is an essential positive regulator in the expansion of CD4+ helper T cells.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

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Ddb1 Is Essential for the Expansion of CD4+ Helper T Cells by Regulating Cell Cycle Progression and Cell Death

Yang

Chen

et al. 2021

Front. Immunol.

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“…Recently, it was shown that neddylated Cul-4b is more abundant after T cell activation, and it is necessary to maintain the survival rate of effector CD4 + T cells. Since Cul-4b lacking CD4 + T cells are not capable of repairing DNA damage, they are more likely to undergo apoptosis ( Dar et al, 2021 ). Taken together, neddylation is an indispensable process for T cells to function properly and survive.…”

Section: Neddylation and Adaptive Immunitymentioning

confidence: 99%

Association Between Neddylation and Immune Response

Zhu

Zhang

Sun

et al. 2022

Front. Cell Dev. Biol.

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Neddylation is a ubiquitin-like post-translational protein modification. It occurs via the activation of the neural precursor cell expressed, developmentally downregulated protein 8 (NEDD8) by three enzymes: activating enzyme, conjugating enzyme, and ligase. NEDD8 was first isolated from the mouse brain in 1992 and was initially considered important for the development and differentiation of the central nervous system. Previously, the downregulation of neddylation was associated with some human diseases, such as neurodegenerative disorders and cancers. In recent years, neddylation has also been proven to be pivotal in various processes of the human immune system, including the regulation of inflammation, bacterial infection, viral infection, and T cell function. Additionally, NEDD8 was found to act on proteins that can affect viral transcription, leading to impaired infectivity. Here, we focused on the influence of neddylation on the innate and adaptive immune responses.

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“…This study revealed Cul4B in promoting the repair of damaged DNA to allow survival and expansion of activated T cells. 20 Hung et al found that myeloid-specific Cul4B deficiency worsens LPS-induced peritonitis, and Cul4B deficiency leads to enhanced DNA replication and proliferation, increased production of chemokines, and decreased proinflammatory production cytokines of macrophages. 21 These results suggested that CUL4B played a crucial role in the immune system.…”

Section: Introductionmentioning

confidence: 99%

CUL4B is a Potential Novel Prognostic Biomarker and is Correlated with Immune Infiltrates in Malignant Pleural Mesothelioma

Liu¹,

Hui²,

Zeng³

et al. 2022

IJGM

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Background Malignant pleural mesothelioma (MPM) is a particularly fatal cancer with a median survival of less than one year. The value of single-agent checkpoint inhibitors is still obscure in MPM. We aim to reveal CUL4B prognostic role and immune infiltrates in MPM patients. Methods CUL4B expression profile and clinical information of malignant pleura mesothelioma individuals were collected from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) dataset. Quantitative real-time PCR (qRT-PCR) analysis measured CUL4B mRNA expression in epithelioid, biphasic, sarcomatoid, and normal pleural cell lines. Results CUL4B expression elevated in MPM and had a high diagnostic value with AUC = 0.772. Additionally, our results showed that CUL4B high expression significantly correlated with poorer outcomes in MPM. Moreover, GSEA revealed 15 KEGG pathways enriched in the CUL4B high-expression group, and 22 were exhibited in the CUL4B low-expression group. Otherwise, our results showed that CUL4B was relevant to Wnt antagonistic factors (BARX2), Insulin-like growth factor binding protein 3 (IGFBP3), and Phosphatase and tensin homolog (PTEN). In addition, our results revealed that CUL4B expression was positively linked with four types of immune cells, whereas CUL4B expression was negatively linked with three types of immune cells. Additionally, our results showed that CUL4B expression regulates T helper cells, Tcm, and Th2 cells infiltration MPM microenvironment. Finally, our results identified CUL4B high expression in MPM cell line NCI-H2052 (epithelioid), MSTO-211H (biphasic), and NCI-H28 (sarcomatoid). Conclusion CUL4B is a valuable prognostic biomarker and a critical immune cell infiltration regulator in MPM.

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The E3 ubiquitin ligase Cul4b promotes CD4+ T cell expansion by aiding the repair of damaged DNA

Cited by 17 publications

References 96 publications

Ddb1 Is Essential for the Expansion of CD4+ Helper T Cells by Regulating Cell Cycle Progression and Cell Death

Ddb1 Is Essential for the Expansion of CD4+ Helper T Cells by Regulating Cell Cycle Progression and Cell Death

Association Between Neddylation and Immune Response

CUL4B is a Potential Novel Prognostic Biomarker and is Correlated with Immune Infiltrates in Malignant Pleural Mesothelioma

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