Kapadia Bandish, Roychowdhury Anirban, Kayastha Forum, Lee Won Sok, Nanaji Nahid, Windle Jolene, Gartenhaus Ronald
Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Section of Hematology and Oncology, Medicine Service, Richmond VA Cancer Center, Richmond Veteran Affairs Medical Center, Richmond, VA, USA; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
Division of Hematology, Oncology, and Palliative Care, Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA; Section of Hematology and Oncology, Medicine Service, Richmond VA Cancer Center, Richmond Veteran Affairs Medical Center, Richmond, VA, USA; VCU Massey Comprehensive Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.
Neoplasia. 2025 Apr;62:101144. doi: 10.1016/j.neo.2025.101144. Epub 2025 Feb 22.
Epitranscriptomic modifications, particularly N6-methyladenosine (m6A), have emerged as critical regulators of RNA stability, localization, and translation, shaping immune responses and tumor progression. In B-cell biology, m6A modifications influence germinal center formation and antigen-driven differentiation, underscoring their importance in immune regulation. Among m6A regulators, ALKBH5 (RNA demethylase) is pivotal in removing methylation marks and modulating gene expression in diverse cellular contexts. Despite advancements in understanding m6A dynamics, the mechanistic interplay between m6A demethylation and B-cell receptor (BCR) signaling pathways still needs to be explored. This study reveals a novel regulatory axis involving ALKBH5, treRNA1 (Translation Regulatory Long Non-Coding RNA 1), and DDX46 (RNA helicase). Upon activation signals, ALKBH5 and treRNA1 translocate to the nucleus, forming a functional complex with DDX46 to orchestrate the removal of m6A modifications on key transcripts, including those involved in BCR signaling. This demethylation enhances transcript stability and facilitates cytoplasmic export through interaction with the RNA-binding protein HuR, promoting efficient translation. Disruption of this axis, via loss of ALKBH5, DDX46, or treRNA1, led to impaired transcript processing and diminished BCR-related gene expression, highlighting the critical role of m6A demethylation in maintaining RNA dynamics. These findings uncover a previously unrecognized epitranscriptomic mechanism driven by the ALKBH5-treRNA1-DDX46 complex, with significant implications for B-cell functionality, immune regulation, and oncogenic pathways. Targeting this axis offers a promising avenue for developing therapeutic strategies in cancer and immune-related disorders where m6A dysregulation plays a central role.
表观转录组修饰，尤其是N6-甲基腺苷（m6A），已成为RNA稳定性、定位和翻译的关键调节因子，影响免疫反应和肿瘤进展。在B细胞生物学中，m6A修饰影响生发中心形成和抗原驱动的分化，凸显了它们在免疫调节中的重要性。在m6A调节因子中，ALKBH5（RNA去甲基化酶）在去除甲基化标记和调节不同细胞环境中的基因表达方面起着关键作用。尽管在理解m6A动态方面取得了进展，但m6A去甲基化与B细胞受体（BCR）信号通路之间的机制相互作用仍有待探索。本研究揭示了一个涉及ALKBH5、treRNA1（翻译调节长链非编码RNA 1）和DDX46（RNA解旋酶）的新型调节轴。在激活信号作用下，ALKBH5和treRNA1易位至细胞核，与DDX46形成功能复合物，以协调去除关键转录本上的m6A修饰，包括那些参与BCR信号传导的转录本。这种去甲基化增强了转录本稳定性，并通过与RNA结合蛋白HuR相互作用促进细胞质输出，从而促进有效翻译。通过缺失ALKBH5、DDX46或treRNA1破坏该轴，会导致转录本加工受损和BCR相关基因表达减少，突出了m6A去甲基化在维持RNA动态中的关键作用。这些发现揭示了一种由ALKBH5-treRNA1-DDX46复合物驱动的前所未有的表观转录组机制，对B细胞功能、免疫调节和致癌途径具有重要意义。针对该轴为开发针对m6A失调起核心作用的癌症和免疫相关疾病的治疗策略提供了一个有前景的途径。
