非规范PRC1.1允许转录反应，使Treg在免疫适应中具有可塑性

IF 14.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cell Pub Date : 2025-06-16 DOI:10.1016/j.molcel.2025.05.029

Ting Li, Yingying Zhao, Qian Li, Zhaoran Sun, Ni Wang, Liangyu Xing, Nan Tang, Runyuan Mao, Yuxin Wang, Jiacheng Su, Dawei Huo, Feng Dong, Xiujuan Zhao, Lei Cao, Yu Kong, Meihan Gong, Ziyi Liu, Wei Li, Xuejiao Lv, Hanhan Ning, Xudong Wu

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引用次数: 0

摘要

多梳抑制复合物（PRCs）通过转录沉默维持调节性T （Treg）细胞的身份，但它们在免疫适应过程中调节Treg功能可塑性的作用尚不清楚。在这里，我们确定了KDM2B，一个非规范PRC1.1的定义成分，作为维持活跃Treg （aTreg）细胞的比例和免疫抑制功能的关键调节因子，而不改变Treg的丰度或特性。从机制上讲，PRC1.1在活性启动子上沉积H2AK119单泛素化（H2AK119ub1），使aTreg程序的转录激活成为可能，而不是抑制。通过Kdm2b消融或选择性抑制剂iBP的药理抑制破坏PRC1.1，可降低H2AK119ub1，减弱刺激依赖性转录激活，并抑制Treg激活。值得注意的是，在患有黑色素瘤的小鼠中，treg特异性Kdm2b缺失增强了抗肿瘤免疫，并与抗pd - l1治疗协同作用。因此，我们的研究强调H2AK119ub1作为双功能表观遗传标记，PRC1.1作为微调Treg适应性的分子变阻器，确立了PRC1.1作为癌症中解耦免疫抑制同时保持Treg稳态的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Non-canonical PRC1.1 licenses transcriptional response to enable Treg plasticity in immune adaptation

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Non-canonical PRC1.1 licenses transcriptional response to enable Treg plasticity in immune adaptation

Polycomb repressive complexes (PRCs) sustain regulatory T (Treg) cell identity through transcriptional silencing, yet their role in modulating Treg functional plasticity during immune adaptation remains unclear. Here, we identify KDM2B, a defining component of non-canonical PRC1.1, as a critical regulator for sustaining the proportion and immunosuppressive functions of active Treg (aTreg) cells without altering Treg abundance or identity. Mechanistically, PRC1.1 deposits H2AK119 monoubiquitylation (H2AK119ub1) at active promoters, enabling rather than repressing transcriptional activation of aTreg programs. Disruption of PRC1.1 via Kdm2b ablation or pharmacological inhibition with iBP, a selective inhibitor, reduces H2AK119ub1, blunts stimulus-dependent transcriptional activation, and suppresses Treg activation. Notably, Treg-specific Kdm2b deletion in melanoma-bearing mice enhances anti-tumor immunity and synergizes with anti-PD-L1 therapy. Therefore, our study underscores H2AK119ub1 as a dual-function epigenetic mark and PRC1.1 as a molecular rheostat fine-tuning Treg adaptability, establishing PRC1.1 as a therapeutic target to decouple immune suppression in cancer while preserving Treg homeostasis.

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来源期刊

Molecular Cell 生物-生化与分子生物学

CiteScore

26.00

自引率

3.80%

发文量

389

审稿时长

1 months

期刊介绍： Molecular Cell is a companion to Cell, the leading journal of biology and the highest-impact journal in the world. Launched in December 1997 and published monthly. Molecular Cell is dedicated to publishing cutting-edge research in molecular biology, focusing on fundamental cellular processes. The journal encompasses a wide range of topics, including DNA replication, recombination, and repair; Chromatin biology and genome organization; Transcription; RNA processing and decay; Non-coding RNA function; Translation; Protein folding, modification, and quality control; Signal transduction pathways; Cell cycle and checkpoints; Cell death; Autophagy; Metabolism.