Huwe1 supports B-cell development, B-cell-dependent immunity, somatic hypermutation and class switch recombination by regulating proliferation

The development and differentiation of B cells is intimately linked to cell proliferation and the generation of diverse immunoglobulin gene ( ) repertoires. The ubiquitin E3 ligase HUWE1 controls proliferation, DNA damage responses, and DNA repair, including the base excision repair (BER) pathway. T...

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Published in:	Frontiers in immunology Vol. 13; p. 986863
Main Authors:	Spanjaard, Aldo, Stratigopoulou, Maria, de Groot, Daniël, Aslam, Muhammad, van den Berk, Paul C M, Stappenbelt, Chantal, Ayidah, Matilda, Catsman, Joyce J I, Pardieck, Iris N, Kreft, Maaike, Arens, Ramon, Guikema, Jeroen E J, Jacobs, Heinz
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 09-01-2023
Subjects:	B-cell B-Lymphocytes Cell Differentiation - genetics development DNA Repair homeostasis HUWE1 immune responses Immunoglobulin Class Switching - genetics Immunology somatic hypermutation Somatic Hypermutation, Immunoglobulin homeostasis development somatic hypermutation B-cell HUWE1 class switch recombination immune responses
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Summary:	The development and differentiation of B cells is intimately linked to cell proliferation and the generation of diverse immunoglobulin gene ( ) 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 gene diversification, focusing on its involvement in somatic hypermutation (SHM) and class switch recombination (CSR). B-cell-specific deletion of 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 and , 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 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.
Bibliography:	Edited by: Yu Nee Lee, Sheba Medical Center, Israel Reviewed by: Javier Marcelo Di Noia, Montreal Clinical Research Institute (IRCM), Canada; Berit Jungnickel, Friedrich Schiller University Jena, Germany These authors contributed equally to this work and share first authorship These authors contributed equally to this work and share third authorship These authors contribute equally to this work and share senior authorship These authors contributed equally to this work and share second authorship This article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology
ISSN:	1664-3224 1664-3224
DOI:	10.3389/fimmu.2022.986863