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 (Ig) repertoires. The ubiquitin E3 ligase HUWE1 controls proliferation, DNA damage responses, and DNA repair, including the base excision repair (BER) pathway....
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-01-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.986863/full |
| _version_ | 1797956851580534784 |
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| author | Aldo Spanjaard Maria Stratigopoulou Daniël de Groot Muhammad Aslam Paul C. M. van den Berk Chantal Stappenbelt Matilda Ayidah Joyce J. I. Catsman Iris N. Pardieck Maaike Kreft Ramon Arens Jeroen E. J. Guikema Heinz Jacobs |
| author_facet | Aldo Spanjaard Maria Stratigopoulou Daniël de Groot Muhammad Aslam Paul C. M. van den Berk Chantal Stappenbelt Matilda Ayidah Joyce J. I. Catsman Iris N. Pardieck Maaike Kreft Ramon Arens Jeroen E. J. Guikema Heinz Jacobs |
| author_sort | Aldo Spanjaard |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T23:55:17Z |
| format | Article |
| id | doaj.art-1d18cf86772b41ecb3b2e4147ddbb1f9 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-10T23:55:17Z |
| publishDate | 2023-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1d18cf86772b41ecb3b2e4147ddbb1f92023-01-10T13:11:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-01-011310.3389/fimmu.2022.986863986863Huwe1 supports B-cell development, B-cell-dependent immunity, somatic hypermutation and class switch recombination by regulating proliferationAldo Spanjaard0Maria Stratigopoulou1Daniël de Groot2Muhammad Aslam3Paul C. M. van den Berk4Chantal Stappenbelt5Matilda Ayidah6Joyce J. I. Catsman7Iris N. Pardieck8Maaike Kreft9Ramon Arens10Jeroen E. J. Guikema11Heinz Jacobs12Division of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, NetherlandsDepartment of Pathology, Amsterdam University Medical Centers, Location Academic Medical Center (AMC), Lymphoma and Myeloma center Amsterdam (LYMMCARE), Amsterdam, NetherlandsDivision of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, NetherlandsDivision of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, NetherlandsDepartment of Immunology, Leiden University Medical Center, Leiden, NetherlandsDivision of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, NetherlandsDepartment of Immunology, Leiden University Medical Center, Leiden, NetherlandsDepartment of Pathology, Amsterdam University Medical Centers, Location Academic Medical Center (AMC), Lymphoma and Myeloma center Amsterdam (LYMMCARE), Amsterdam, NetherlandsDivision of Tumor Biology and Immunology, Netherlands Cancer Institute, Amsterdam, NetherlandsThe 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.https://www.frontiersin.org/articles/10.3389/fimmu.2022.986863/fullHUWE1B-cellimmune responseshomeostasisdevelopmentsomatic hypermutation |
| spellingShingle | Aldo Spanjaard Maria Stratigopoulou Daniël de Groot Muhammad Aslam Paul C. M. van den Berk Chantal Stappenbelt Matilda Ayidah Joyce J. I. Catsman Iris N. Pardieck Maaike Kreft Ramon Arens Jeroen E. J. Guikema Heinz Jacobs Huwe1 supports B-cell development, B-cell-dependent immunity, somatic hypermutation and class switch recombination by regulating proliferation Frontiers in Immunology HUWE1 B-cell immune responses homeostasis development somatic hypermutation |
| title | Huwe1 supports B-cell development, B-cell-dependent immunity, somatic hypermutation and class switch recombination by regulating proliferation |
| title_full | Huwe1 supports B-cell development, B-cell-dependent immunity, somatic hypermutation and class switch recombination by regulating proliferation |
| title_fullStr | Huwe1 supports B-cell development, B-cell-dependent immunity, somatic hypermutation and class switch recombination by regulating proliferation |
| title_full_unstemmed | Huwe1 supports B-cell development, B-cell-dependent immunity, somatic hypermutation and class switch recombination by regulating proliferation |
| title_short | Huwe1 supports B-cell development, B-cell-dependent immunity, somatic hypermutation and class switch recombination by regulating proliferation |
| title_sort | huwe1 supports b cell development b cell dependent immunity somatic hypermutation and class switch recombination by regulating proliferation |
| topic | HUWE1 B-cell immune responses homeostasis development somatic hypermutation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.986863/full |
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