TY - JOUR
T1 - Huwe1 supports B-cell development, B-cell-dependent immunity, somatic hypermutation and class switch recombination by regulating proliferation
AU - Spanjaard, Aldo
AU - Stratigopoulou, Maria
AU - de Groot, Dani?l
AU - Aslam, Muhammad
AU - van den Berk, Paul C. M.
AU - Stappenbelt, Chantal
AU - Ayidah, Matilda
AU - Catsman, Joyce J. I.
AU - Pardieck, Iris N.
AU - Kreft, Maaike
AU - Arens, Ramon
AU - Guikema, Jeroen E. J.
AU - Jacobs, Heinz
N1 - Funding Information: This work was supported and made possible by two grants from the Dutch cancer foundation; KWF NKI-2017– 10032 and NKI2017-10796 to HJ, and by the COSMIC project that has received funding from the EU Horizon 2020 and the innovation program under the Marie Skłodowska-Curie grant agreement No. 765158. to JG. Acknowledgments Publisher Copyright: Copyright © 2023 Spanjaard, Stratigopoulou, de Groot, Aslam, van den Berk, Stappenbelt, Ayidah, Catsman, Pardieck, Kreft, Arens, Guikema and Jacobs.
PY - 2023/1/9
Y1 - 2023/1/9
N2 - The development and differentiation of B cells is intimately linked to cell proliferation and the generation of diverse immunoglobulin gene (Ig) repertoires. The ubiquitin E3 ligase HUWE1 controls proliferation, DNA damage responses, and DNA repair, including the base excision repair (BER) pathway. These processes are of crucial importance for B-cell development in the bone marrow, and the germinal center (GC) response, which results in the clonal expansion and differentiation of B cells expressing high affinity immunoglobulins. Here, we re-examined the role of HUWE1 in B-cell proliferation and Ig gene diversification, focusing on its involvement in somatic hypermutation (SHM) and class switch recombination (CSR). B-cell-specific deletion of Huwe1 resulted in impaired development, differentiation and maturation of B cells in the bone marrow and peripheral lymphoid organs. HUWE1 deficiency diminished SHM and CSR by impairing B-cell proliferation and AID expression upon activation in vitro and in vivo, and was unrelated to the HUWE1-dependent regulation of the BER pathway. Interestingly, we found that HUWE1-deficient B cells showed increased mRNA expression of Myc target genes upon in vitro activation despite diminished proliferation. Our results confirm that the E3 ligase HUWE1 is an important contributor in coordinating the rapid transition of antigen naïve, resting B cells into antigen-activated B cells and regulates mutagenic processes in B cells by controlling AID expression and the post-transcriptional output of Myc target genes.
AB - The development and differentiation of B cells is intimately linked to cell proliferation and the generation of diverse immunoglobulin gene (Ig) repertoires. The ubiquitin E3 ligase HUWE1 controls proliferation, DNA damage responses, and DNA repair, including the base excision repair (BER) pathway. These processes are of crucial importance for B-cell development in the bone marrow, and the germinal center (GC) response, which results in the clonal expansion and differentiation of B cells expressing high affinity immunoglobulins. Here, we re-examined the role of HUWE1 in B-cell proliferation and Ig gene diversification, focusing on its involvement in somatic hypermutation (SHM) and class switch recombination (CSR). B-cell-specific deletion of Huwe1 resulted in impaired development, differentiation and maturation of B cells in the bone marrow and peripheral lymphoid organs. HUWE1 deficiency diminished SHM and CSR by impairing B-cell proliferation and AID expression upon activation in vitro and in vivo, and was unrelated to the HUWE1-dependent regulation of the BER pathway. Interestingly, we found that HUWE1-deficient B cells showed increased mRNA expression of Myc target genes upon in vitro activation despite diminished proliferation. Our results confirm that the E3 ligase HUWE1 is an important contributor in coordinating the rapid transition of antigen naïve, resting B cells into antigen-activated B cells and regulates mutagenic processes in B cells by controlling AID expression and the post-transcriptional output of Myc target genes.
KW - B-cell
KW - HUWE1
KW - class switch recombination
KW - development
KW - homeostasis
KW - immune responses
KW - somatic hypermutation
UR - http://www.scopus.com/inward/record.url?scp=85146875773&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fimmu.2022.986863
DO - https://doi.org/10.3389/fimmu.2022.986863
M3 - Article
C2 - 36700204
SN - 1664-3224
VL - 13
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 986863
ER -