A SIRT7-dependent acetylation switch regulates early B cell differentiation and lineage commitment through Pax5
Year: 2024
Type: article
Abstract: 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 Pax5K198 deacetylated nor acetylated mimics rescued B cell differentiation in Pax5−/− pro-B cells, suggesting that B cell development requires Pax5 dynamic deacetylation. The Pax5K198 deacetylation mimic restored lineage commitment in Pax5−/− pro-B cells and B cell differentiation in Sirt7−/− 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.
Source: Nature Immunology
Authors: Andres Gamez-Garcia, Maria Espinosa-Alcantud, Alberto Bueno-Costa, Elisenda Alari-Pahissa, Anna Marazuela-Duque, Joshua K. Thackray, Chandni Ray, Clara Berenguer, Poonam Kumari, Joan Josep Bech, Thomas Braun, Alessandro Ianni, Jay A. Tischfield, Lourdes Serrano, Manel Esteller, Jose L. Sardina, Carolina De La Torre, Mikael Sigvardsson, Berta N. Vazquez, Alejandro Vaquero
Institutions: Josep Carreras Leukaemia Research Institute, Universitat Pompeu Fabra, Rutgers, The State University of New Jersey, Max Planck Institute for Heart and Lung Research, Institució Catalana de Recerca i Estudis Avançats, Centro de Investigación Biomédica en Red de Cáncer, Universitat de Barcelona, Lund University, Universitat Autònoma de Barcelona
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,290
Funders: Swedish Cancer Foundation, Centres de Recerca de Catalunya, European Commission, Fundación Científica Asociación Española Contra el Cáncer, Generalitat de Catalunya, Departament d'Innovació, Universitats i Empresa, Generalitat de Catalunya, Ministerio de Economía y Competitividad, Vetenskapsrådet, Barncancerfonden, Forskningsrådet om Hälsa, Arbetsliv och Välfärd, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, Agencia Estatal de Investigación, National Cancer Institute
Awards: G1312037434, G1485110706, G1886494958, G2262748287, G3005324705, G3480869486, G3681454997, G3684056134, G374079859, G4042783231, G425668148, Molecular analysis of leukemia mediated alternations in normal blood cell development ., G488635281, G5830402311, G58477064, G5852091828, Mechanisms of Sirtuin-dependent regulation of immunity and leukemogenesis, G6656126374, G6678253513, G6702250933, G6741787527, G7084143925, G7425137858, G7578143225, G7721946649, G8234372533, G8430294048, G8684520763, G888663958
OpenAlex ID: W4403547478