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

Frontiers in Immunology, vol. 13, pp. 986863

Abstract

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.

Authors 13

1. Aldo Spanjaard

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands

2. Maria Stratigopoulou

   Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers

   Affiliation as printed

   Department of Pathology, Amsterdam University Medical Centers, Location Academic Medical Center (AMC), Lymphoma and Myeloma center Amsterdam (LYMMCARE), Amsterdam, Netherlands

3. Daniël de Groot

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands

4. Muhammad Assad Aslam

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands

5. Paul C.M. van den Berk

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands

6. Chantal Stappenbelt

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands

7. Matilda Ayidah

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands

8. Joyce J. I. Catsman

   The Netherlands Cancer Institute

   Affiliation as printed

   Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands

9. Iris N. Pardieck Aachen Department of Immunology, Leiden University Medical Center

   Leiden University Medical Center

   Affiliation as printed

   Department of Immunology, Leiden University Medical Center, Leiden, Netherlands

10. Maaike Kreft

    The Netherlands Cancer Institute

    Affiliation as printed

    Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands

11. Ramon Arens Aachen Department of Immunology, Leiden University Medical Center

    Leiden University Medical Center

    Affiliation as printed

    Department of Immunology, Leiden University Medical Center, Leiden, Netherlands

12. Jeroen E. J. Guikema corresponding

    Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers

    Affiliation as printed

    Department of Pathology, Amsterdam University Medical Centers, Location Academic Medical Center (AMC), Lymphoma and Myeloma center Amsterdam (LYMMCARE), Amsterdam, Netherlands

13. Heinz Jacobs corresponding

    The Netherlands Cancer Institute

    Affiliation as printed

    Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands