biostudies-literatureGamez-Garcia ABarncancerfonden (Swedish Childhood Cancer Foundation)EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 Marie Skłodowska-Curie Actions (H2020 Excellent Science - Marie Skłodowska-Curie Actions)Forskningsrådet om Hälsa, Arbetsliv och Välfärd (Swedish Research Council for Health, Working Life and Welfare)Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya (Department of Innovation, Education and Enterprise, Government of Catalonia)Fundación Científica Asociación Española Contra el Cáncer (Scientific Foundation, Spanish Association Against Cancer)Ministry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)2308-2319https://www.ebi.ac.uk/biostudies/studies/S-EPMC11588656biostudies-literatureUnknown25(12)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⁺-dependent enzyme SIRT7 coordinates B cell development through deacetylation of Pax5 at K198, which promotes Pax5 protein stability and transcriptional activity. Neither Pax5^K198 deacetylated nor acetylated mimics rescued B cell differentiation in Pax5^-/- pro-B cells, suggesting that B cell development requires Pax5 dynamic deacetylation. The Pax5^K198 deacetylation mimic restored lineage commitment in Pax5<sup>-/-</sNature immunologyA SIRT7-dependent acetylation switch regulates early B cell differentiation and lineage commitment through Pax5.PMC11588656MSC-2021-1010650132021-SGR-014942022-0019PROYE20042VAQUFI_B 002932017-SGR-1482021-02379SAF2017-88975RMSC-2020-8959792021-SGR-013782016-BP-00250Gamez-Garcia ABueno-Costa ASigvardsson MAlari-Pahissa EBerenguer CTischfield JAEsteller MEspinosa-Alcantud MDe La Torre CBech JJBraun TVaquero AVazquez BNMarazuela-Duque AThackray JKKumari PRay CIanni ASerrano LSardina JLfalseA 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⁺-dependent enzyme SIRT7 coordinates B cell development through deacetylation of Pax5 at K198, which promotes Pax5 protein stability and transcriptional activity. Neither Pax5^K198 deacetylated nor acetylated mimics rescued B cell differentiation in Pax5^-/- pro-B cells, suggesting that B cell development requires Pax5 dynamic deacetylation. The Pax5^K198 deacetylation mimic restored lineage commitment in Pax5<sup>-/-</s2024-01-01T00:00:00Z2024 Dec2026-06-02T22:57:02.649Z2025-04-21T21:42:49.289ZS-EPMC115886563942498510.1038/s41590-024-01995-7