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The miR-17∼92 miRNAs promote plasma cell differentiation by suppressing SOCS3-mediated NIK degradation
Cell Reports ( IF 7.5 ) Pub Date : 2023-08-13 , DOI: 10.1016/j.celrep.2023.112968
Jun Xie 1 , Ying Du 1 , Dewang Liu 1 , Jianfeng Wu 1 , Kang Yang 1 , Xiaoyu He 1 , Jiayi Zhao 1 , Peicheng Hong 1 , Kunyu Liao 1 , Huanrong Zhang 1 , Yazhen Hong 1 , John R Teijaro 2 , Seung Goo Kang 3 , Changchun Xiao 4 , Wen-Hsien Liu 1
Cell Reports ( IF 7.5 ) Pub Date : 2023-08-13 , DOI: 10.1016/j.celrep.2023.112968
Jun Xie 1 , Ying Du 1 , Dewang Liu 1 , Jianfeng Wu 1 , Kang Yang 1 , Xiaoyu He 1 , Jiayi Zhao 1 , Peicheng Hong 1 , Kunyu Liao 1 , Huanrong Zhang 1 , Yazhen Hong 1 , John R Teijaro 2 , Seung Goo Kang 3 , Changchun Xiao 4 , Wen-Hsien Liu 1
Affiliation
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The miR-17∼92 family microRNAs (miRNAs) play a key role in germinal center (GC) reaction through promoting T follicular helper (T) cell differentiation. It remains unclear whether they also have intrinsic functions in B cell differentiation and function. Here we show that mice with B cell-specific deletion of the miR-17∼92 family exhibit impaired GC reaction, plasma cell differentiation, and antibody production in response to protein antigen immunization and chronic viral infection. Employing CRISPR-mediated functional screening, we identify as a key functional target of miR-17∼92 in regulating plasma cell differentiation. Mechanistically, SOCS3, whose expression is elevated in miR-17∼92 family-deficient B cells, interacts with NIK and promotes its ubiquitination and degradation, thereby impairing NF-κB signaling and plasma cell differentiation. This moderate increase in SOCS3 expression has little effect on IL-21-STAT3 signaling. Our study demonstrates differential sensitivity of two key signaling pathways to alterations in the protein level of an miRNA target gene.
中文翻译：
miR-17∼92 miRNA通过抑制SOCS3介导的NIK降解促进浆细胞分化
miR-17∼92 家族 microRNA (miRNA) 通过促进滤泡辅助 (T) 细胞分化，在生发中心 (GC) 反应中发挥关键作用。目前尚不清楚它们是否在 B 细胞分化和功能中也具有内在功能。在这里，我们发现，B 细胞特异性删除 miR-17∼92 家族的小鼠在蛋白质抗原免疫和慢性病毒感染时表现出 GC 反应、浆细胞分化和抗体产生受损。采用 CRISPR 介导的功能筛选，我们确定了 miR-17∼92 是调节浆细胞分化的关键功能靶点。从机制上讲，SOCS3在miR-17∼92家族缺陷的B细胞中表达升高，与NIK相互作用并促进其泛素化和降解，从而损害NF-κB信号传导和浆细胞分化。 SOCS3 表达的适度增加对 IL-21-STAT3 信号传导影响很小。我们的研究证明了两个关键信号通路对 miRNA 靶基因蛋白质水平变化的不同敏感性。
更新日期：2023-08-13
中文翻译：
miR-17∼92 miRNA通过抑制SOCS3介导的NIK降解促进浆细胞分化
miR-17∼92 家族 microRNA (miRNA) 通过促进滤泡辅助 (T) 细胞分化，在生发中心 (GC) 反应中发挥关键作用。目前尚不清楚它们是否在 B 细胞分化和功能中也具有内在功能。在这里，我们发现，B 细胞特异性删除 miR-17∼92 家族的小鼠在蛋白质抗原免疫和慢性病毒感染时表现出 GC 反应、浆细胞分化和抗体产生受损。采用 CRISPR 介导的功能筛选，我们确定了 miR-17∼92 是调节浆细胞分化的关键功能靶点。从机制上讲，SOCS3在miR-17∼92家族缺陷的B细胞中表达升高，与NIK相互作用并促进其泛素化和降解，从而损害NF-κB信号传导和浆细胞分化。 SOCS3 表达的适度增加对 IL-21-STAT3 信号传导影响很小。我们的研究证明了两个关键信号通路对 miRNA 靶基因蛋白质水平变化的不同敏感性。
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