期刊
MOLECULAR CANCER
卷 20, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s12943-021-01399-3
关键词
RIPK3; TRIM28; NF-kappa B; Transcriptional regulator; Chromatin; Immunostimulatory cytokines
资金
- National Research Foundation of Korea [2017R1A2B3002343, 2021R1A4A1031856]
- Brain Korea 21 FOUR program for Leading Universities & Students - Korean government
- INHA UNIVERSITY Research Grant
- National Research Foundation of Korea [4199990314020] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
The study identifies TRIM28 as a co-repressor regulating transcriptional activity during necroptosis. Activated RIPK3 phosphorylates TRIM28, inhibiting its chromatin binding activity and contributing to increased cytokine expression and immunoregulatory processes. RIPK3 activation-dependent derepression of TRIM28 in cancer cells leads to enhanced immunostimulatory cytokine production and robust anti-tumor immunity.
Background: Necroptosis is emerging as a new target for cancer immunotherapy as it is now recognized as a form of cell death that increases tumor immunogenicity, which would be especially helpful in treating immune-desert tumors. De novo synthesis of inflammatory proteins during necroptosis appears especially important in facilitating increased anti-tumor immune responses. While late-stage transcription mediated by NF-kappa B during cell death is believed to play a role in this process, it is otherwise unclear what cell signaling events initiate this transactivation of inflammatory genes. Methods: We employed tandem-affinity purification linked to mass spectrometry (TAP-MS), in combination with the analysis of RNA-sequencing (RNA-Seq) datasets to identify the Tripartite Motif Protein 28 (TRIM28) as a candidate co-repressor. Comprehensive biochemical and molecular biology techniques were used to characterize the role of TRIM28 in RIPK3 activation-induced transcriptional and immunomodulatory events. The cell composition estimation module was used to evaluate the correlation between RIPK3/TRIM28 levels and CD8(+) T cells or dendritic cells (DC) in all TCGA tumors. Results: We identified TRIM28 as a co-repressor that regulates transcriptional activity during necroptosis. Activated RIPK3 phosphorylates TRIM28 on serine 473, inhibiting its chromatin binding activity, thereby contributing to the transactivation of NF-kappa B and other transcription factors, such as SOX9. This leads to elevated cytokine expression, which then potentiates immunoregulatory processes, such as DC maturation. The expression of RIPK3 has a significant positive association with the tumor-infiltrating immune cells populations in various tumor type, thereby activating anti-cancer responses. Conclusion: Our data suggest that RIPK3 activation-dependent derepression of TRIM28 in cancer cells leads to increased immunostimulatory cytokine production in the tumor microenvironment, which then contributes to robust cytotoxic anti-tumor immunity.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据