MiR-17∼92 is involved in NF-κB activation via targeting the ubiquitin-editing proteins to mediate RIP1 complex polyubiquitinations in ABC-DLBCL

IF 4.5 3区 医学 Q2 IMMUNOLOGY Clinical immunology Pub Date : 2024-06-22 DOI:10.1016/j.clim.2024.110297
Xiaoyan Zhang , Xuan Zhang , Xin Huang , Javeed Iqbal , Timothy W. McKeithan , Wing C. Chan , Julie M. Vose , Chengfeng Bi , Xiaofan Zhu , Kai Fu
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Abstract

Activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) is an aggressive lymphoma characterized by constitutive NF-κB activation, but whether miR-17∼92 contributes to this activation remains unclear. Herein, we sought to evaluate the role of miR-17∼92 in the process of NF-κB activation in ABC-DLBCL. We found that the expression of miR-17∼92 primary transcript was positively correlated with NF-κB activity, miR-17∼92 activated the NF-κB signaling in ABC-DLBCL, and its over-expression promoted ABC-DLBCL cell growth, accelerated cell G1 to S phase transition and enhanced cell resistance to NF-κB inhibitor. Importantly, miR-17∼92 promoted NF-κB activation through directly targeting multiple ubiquitin-editing regulators to lead to increase the K63-linked polyubiquitination and decrease the K48-linked polyubiquitination of RIP1 complex in ABC-DLBCL. We further found that miR-17∼92 selectively activated IκB-α and NF-κB p65 but not NF-κB p52/p100, and high miR-17∼92 expression was also associated with poorer outcome in ABC-DLBCL patients. Overall, our results showed that miR-17∼92 selectively activated the canonical NF-κB signaling via targeting ubiquitin-editing regulators to lead to constitutively NF-κB activation and poorer outcome in ABC-DLBCL. These findings uncovered an innovative function of miR-17∼92 and previously unappreciated regulatory mechanism of NF-κB activation in ABC-DLBCL. Targeting miR-17∼92 may thus provide a novel bio-therapeutic strategy for ABC-DLBCL patients.

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在 ABC-DLBCL 中,MiR-17~92 通过靶向泛素编辑蛋白介导 RIP1 复合物多泛素化参与 NF-κB 激活。
活化B细胞样弥漫大B细胞淋巴瘤(ABC-DLBCL)是一种侵袭性淋巴瘤,其特点是构成性NF-κB活化,但miR-17~92是否有助于这种活化仍不清楚。在此,我们试图评估 miR-17~92 在 ABC-DLBCL 中 NF-κB 激活过程中的作用。我们发现,miR-17~92主转录本的表达与NF-κB活性呈正相关,miR-17~92激活了ABC-DLBCL中的NF-κB信号转导,它的过度表达促进了ABC-DLBCL细胞的生长,加速了细胞G1期向S期的转变,增强了细胞对NF-κB抑制剂的抵抗力。重要的是,miR-17~92 通过直接靶向多个泛素编辑调节因子,导致 ABC-DLBCL 中 RIP1 复合物的 K63 连接泛素化增加和 K48 连接泛素化减少,从而促进了 NF-κB 的激活。我们进一步发现,miR-17~92能选择性地激活IκB-α和NF-κB p65,但不能激活NF-κB p52/p100,而且miR-17~92的高表达与ABC-DLBCL患者较差的预后有关。总之,我们的研究结果表明,miR-17~92通过靶向泛素编辑调节因子选择性地激活了典型的NF-κB信号传导,从而导致了ABC-DLBCL患者NF-κB的组成性激活和较差的预后。这些发现揭示了miR-17~92的创新功能,以及之前未被认识到的ABC-DLBCL中NF-κB激活的调控机制。因此,靶向miR-17~92可为ABC-DLBCL患者提供一种新的生物治疗策略。
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来源期刊
Clinical immunology
Clinical immunology 医学-免疫学
CiteScore
12.30
自引率
1.20%
发文量
212
审稿时长
34 days
期刊介绍: Clinical Immunology publishes original research delving into the molecular and cellular foundations of immunological diseases. Additionally, the journal includes reviews covering timely subjects in basic immunology, along with case reports and letters to the editor.
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