A SIRT7-dependent acetylation switch regulates early B cell differentiation and lineage commitment through Pax5
B lymphopoiesis is orchestrated by lineage-specific transcription factors. In B cell progenitors, lineage commitment is mediated by Pax5, which is commonly mutated in B cell acute lymphoblastic leukemia. Despite its essential role in immunity, the mechanisms regulating Pax5 function remain largely unknown. Here, we found that the NAD<sup>+</sup>-dependent enzyme SIRT7 coordinates B cell development through deacetylation of Pax5 at K198, which promotes Pax5 protein stability and transcriptional activity. Neither Pax5<sup>K198</sup> deacetylated nor acetylated mimics rescued B cell differentiation in Pax5<sup>-/-</sup> pro-B cells, suggesting that B cell development requires Pax5 dynamic deacetylation. The Pax5<sup>K198</sup> deacetylation mimic restored lineage commitment in Pax5<sup>-/-</sup> pro-B cells and B cell differentiation in Sirt7<sup>-/-</sup> pro-B cells, suggesting the uncoupling of differentiation from lineage commitment. The SIRT7-Pax5 interplay was conserved in B cell acute lymphoblastic leukemia, where SIRT7 expression correlated with good prognosis. Our findings reveal a crucial mechanism for B lymphopoiesis and highlight the relevance of sirtuins in immune function.
Authors
- Berta N. Vázquez (ORCID: https://orcid.org/0000-0002-8164-3926)
- Alessandro Ianni (ORCID: https://orcid.org/0000-0001-7398-589X)
- Manel Esteller (ORCID: https://orcid.org/0000-0003-4490-6093)
- Anna Marazuela-Duque
- Clara Berenguer (ORCID: https://orcid.org/0000-0003-4190-8085)
- Mikael Sigvardsson (ORCID: https://orcid.org/0000-0001-8527-7276)
- Jay A. Tischfield (ORCID: https://orcid.org/0000-0003-3217-8287)
- Joan Josep Bech‐Serra (ORCID: https://orcid.org/0000-0003-3486-781X)
- Thomas Braun (ORCID: https://orcid.org/0000-0002-6165-4804)
- Lourdes Serrano (ORCID: https://orcid.org/0000-0002-3409-9366)
- José Luis Sardina (ORCID: https://orcid.org/0000-0002-8493-3937)
- Joshua K. Thackray (ORCID: https://orcid.org/0000-0003-2828-452X)
- Andrés Gámez-García (ORCID: https://orcid.org/0000-0003-4927-3678)
- Chandni Ray
- Alberto Bueno-Costa (ORCID: https://orcid.org/0000-0001-8700-2540)
- Elisenda Alari‐Pahissa (ORCID: https://orcid.org/0000-0001-7424-5383)
- Maria Espinosa‐Alcantud (ORCID: https://orcid.org/0000-0002-1126-2458)
- Carolina de la Torre (ORCID: https://orcid.org/0000-0001-9363-291X)
- Poonam Kumari (ORCID: https://orcid.org/0000-0001-9646-2426)
- Alejandro Vaquero (ORCID: https://orcid.org/0000-0002-8735-4156)
Institutions
- Rutgers, The State University of New Jersey (US)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Universitat Autònoma de Barcelona (ES)
- Universitat Pompeu Fabra (ES)
- Lund University (SE)
- Josep Carreras Leukaemia Research Institute (ES)
- Max Planck Institute for Heart and Lung Research (DE)
- Centro de Investigación Biomédica en Red de Cáncer (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- Nature Immunology
- Published
- 2024-10-18
- DOI
- https://doi.org/10.1038/s41590-024-01995-7
- Citations
- 13
- Primary Topic
- Cytomegalovirus and herpesvirus research
- Type
- article
- Field-Weighted Citation Impact
- 5.03
Funders
- Swedish Cancer Foundation
- Centres de Recerca de Catalunya
- European Commission
- Generalitat de Catalunya
- Ministerio de Economía y Competitividad
- Vetenskapsrådet
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Instituto de Salud Carlos III
- Agencia Estatal de Investigación
- National Cancer Institute