B-cell intrinsic regulation of antibody mediated immunity by histone H2A deubiquitinase BAP1

Front Immunol. 2024 Mar 11:15:1353138. doi: 10.3389/fimmu.2024.1353138. eCollection 2024.

Abstract

Introduction: BAP1 is a deubiquitinase (DUB) of the Ubiquitin C-terminal Hydrolase (UCH) family that regulates gene expression and other cellular processes, through its direct catalytic activity on the repressive epigenetic mark histone H2AK119ub, as well as on several other substrates. BAP1 is also a highly important tumor suppressor, expressed and functional across many cell types and tissues. In recent work, we demonstrated a cell intrinsic role of BAP1 in the B cell lineage development in murine bone marrow, however the role of BAP1 in the regulation of B cell mediated humoral immune response has not been previously explored.

Methods and results: In the current study, we demonstrate that a B-cell intrinsic loss of BAP1 in activated B cells in the Bap1 fl/fl Cγ1-cre murine model results in a severe defect in antibody production, with altered dynamics of germinal centre B cell, memory B cell, and plasma cell numbers. At the cellular and molecular level, BAP1 was dispensable for B cell immunoglobulin class switching but resulted in an impaired proliferation of activated B cells, with genome-wide dysregulation in histone H2AK119ub levels and gene expression.

Conclusion and discussion: In summary, our study establishes the B-cell intrinsic role of BAP1 in antibody mediated immune response and indicates its central role in the regulation of the genome-wide landscapes of histone H2AK119ub and downstream transcriptional programs of B cell activation and humoral immunity.

Keywords: B cell; class switch recombination; deubiquinating enzymes; epigenetic regulation and gene expression; germinal center (GC) B cells; humoral immune response; mouse model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / metabolism
  • B-Lymphocytes* / immunology
  • B-Lymphocytes* / metabolism
  • Histones / metabolism
  • Mice
  • Tumor Suppressor Proteins* / genetics
  • Tumor Suppressor Proteins* / metabolism
  • Ubiquitin Thiolesterase* / genetics
  • Ubiquitin Thiolesterase* / metabolism

Substances

  • Antibodies
  • BAP1 protein, mouse
  • Histones
  • Tumor Suppressor Proteins
  • Ubiquitin Thiolesterase

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. The work was funded by the Discovery Grant RGPIN-2016-05657 from the Natural Sciences and Engineering Research Council of Canada (NSERC). Work by NS and JN was funded by project grant PJ-155944 from the Canadian Institutes of Health Research (CIHR). AN is a Canada Research Chair Tier II in Hematopoiesis and Lymphocyte Differentiation; YL was a recipient of the Richard Birks Fellowship (2017), Internal Scholarship from the Faculty of Medicine of McGill University (2020), and Ph.D. Studentship from the Fonds de Recherche du Québec - Santé (FRQS, 2021-2024); DL was supported by an FRQS Junior 1 salary award; HW was a recipient of an FRQS Masters Training Studentship (2018-2020); NSJ holds an FRQS Doctoral Training Scholarship (2020-2024); LT was a recipient of the Richard Birks Fellowship (2020), Cole Foundation Studentship (2021), and CIHR Canada Graduate Scholarship (2022-2025); YHL was a recipient of Frederick Banting Tri-Council Scholarship (2017), Cole Foundation Studentship (2018-2020), and FRQS Doctoral Training Scholarship (2020).