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...
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| Published in: | Frontiers in immunology Vol. 13; p. 986863 |
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09.01.2023
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| 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. |
|---|---|
| AbstractList | 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. 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.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. 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. 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. |
| Author | Stratigopoulou, Maria Stappenbelt, Chantal Arens, Ramon Pardieck, Iris N. Guikema, Jeroen E. J. Aslam, Muhammad van den Berk, Paul C. M. Kreft, Maaike Jacobs, Heinz Catsman, Joyce J. I. Spanjaard, Aldo de Groot, Daniël Ayidah, Matilda |
| AuthorAffiliation | 2 Department of Pathology, Amsterdam University Medical Centers, Location Academic Medical Center (AMC), Lymphoma and Myeloma center Amsterdam (LYMMCARE) , Amsterdam , Netherlands 3 Department of Immunology, Leiden University Medical Center , Leiden , Netherlands 1 Division of Tumor Biology and Immunology, Netherlands Cancer Institute , Amsterdam , Netherlands |
| AuthorAffiliation_xml | – name: 1 Division of Tumor Biology and Immunology, Netherlands Cancer Institute , Amsterdam , Netherlands – name: 2 Department of Pathology, Amsterdam University Medical Centers, Location Academic Medical Center (AMC), Lymphoma and Myeloma center Amsterdam (LYMMCARE) , Amsterdam , Netherlands – name: 3 Department of Immunology, Leiden University Medical Center , Leiden , Netherlands |
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| Cites_doi | 10.1038/nri3804 10.1038/sj.onc.1205129 10.1084/jem.20111363 10.1101/2020.01.30.926964 10.1073/pnas.1008589107 10.1038/emboj.2009.243 10.1038/ncomms6513 10.15252/embr.201541685 10.1038/ni.3559 10.1016/j.leukres.2013.09.009 10.1016/j.febslet.2011.03.069 10.1016/j.immuni.2019.07.001 10.1016/j.bbrc.2013.12.053 10.1074/jbc.M111.322867 10.1016/j.immuni.2016.09.001 10.1073/pnas.0502779102 10.1084/jem.20070902 10.15252/embr.202051184 10.1371/journal.pone.0008883 10.4049/jimmunol.179.9.6064 10.1091/mbc.e07-02-0173 10.1016/j.molcel.2020.12.035 10.1084/jem.20070756 10.1016/j.dnarep.2011.08.005 10.1016/j.cell.2005.08.016 10.3389/fimmu.2019.00438 |
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| Copyright | Copyright © 2023 Spanjaard, Stratigopoulou, de Groot, Aslam, van den Berk, Stappenbelt, Ayidah, Catsman, Pardieck, Kreft, Arens, Guikema and Jacobs. Copyright © 2023 Spanjaard, Stratigopoulou, de Groot, Aslam, van den Berk, Stappenbelt, Ayidah, Catsman, Pardieck, Kreft, Arens, Guikema and Jacobs 2023 Spanjaard, Stratigopoulou, de Groot, Aslam, van den Berk, Stappenbelt, Ayidah, Catsman, Pardieck, Kreft, Arens, Guikema and Jacobs |
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| Keywords | homeostasis development somatic hypermutation B-cell HUWE1 class switch recombination immune responses |
| Language | English |
| License | Copyright © 2023 Spanjaard, Stratigopoulou, de Groot, Aslam, van den Berk, Stappenbelt, Ayidah, Catsman, Pardieck, Kreft, Arens, Guikema and Jacobs. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 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 |
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| Snippet | The development and differentiation of B cells is intimately linked to cell proliferation and the generation of diverse immunoglobulin gene (
Ig
) repertoires.... The development and differentiation of B cells is intimately linked to cell proliferation and the generation of diverse immunoglobulin gene ( ) repertoires.... The development and differentiation of B cells is intimately linked to cell proliferation and the generation of diverse immunoglobulin gene (Ig) repertoires.... |
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| SubjectTerms | B-cell B-Lymphocytes Cell Differentiation - genetics development DNA Repair homeostasis HUWE1 immune responses Immunoglobulin Class Switching - genetics Immunology somatic hypermutation Somatic Hypermutation, Immunoglobulin |
| Title | Huwe1 supports B-cell development, B-cell-dependent immunity, somatic hypermutation and class switch recombination by regulating proliferation |
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