The miR-17∼92 miRNAs promote plasma cell differentiation by suppressing SOCS3-mediated NIK degradation
- Cell Rep. 2023 Aug 13;42(8):112968. doi: 10.1016/j.celrep.2023.112968.
- 1. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
- 2. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.
- 3. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA; Division of Biomedical Convergence/Institute of Bioscience and Biotechnology, College of Biomedical Science, Kangwon National University, Chuncheon 24341, Republic of Korea. Electronic address: [email protected].
- 4. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA. Electronic address: [email protected].
- 5. State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: [email protected].
The miR-17∼92 family MicroRNAs (miRNAs) play a key role in germinal center (GC) reaction through promoting T follicular helper (TFH) 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 Socs3 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.