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A SIRT7-dependent acetylation switch regulates early B cell differentiation and lineage commitment through Pax5

Gamez-Garcia, Andres ; Espinosa-Alcantud, Maria ; Bueno-Costa, Alberto ; Alari-Pahissa, Elisenda ; Marazuela-Duque, Anna ; Thackray, Joshua K. ; Ray, Chandni ; Berenguer, Clara ; Kumari, Poonam and Bech, Joan Josep , et al. (2024) In Nature Immunology 25(12). p.2308-2319
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Immunology
volume
25
issue
12
pages
12 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:39424985
  • scopus:85206997997
ISSN
1529-2908
DOI
10.1038/s41590-024-01995-7
language
English
LU publication?
yes
additional info
Publisher Copyright: © The Author(s) 2024.
id
b6026895-733b-4e5f-98f1-caba41d76fac
date added to LUP
2024-12-18 17:14:08
date last changed
2025-05-22 06:08:49
@article{b6026895-733b-4e5f-98f1-caba41d76fac,
  abstract     = {{<p>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.</p>}},
  author       = {{Gamez-Garcia, Andres and Espinosa-Alcantud, Maria and Bueno-Costa, Alberto and Alari-Pahissa, Elisenda and Marazuela-Duque, Anna and Thackray, Joshua K. and Ray, Chandni and Berenguer, Clara and Kumari, Poonam and Bech, Joan Josep and Braun, Thomas and Ianni, Alessandro and Tischfield, Jay A. and Serrano, Lourdes and Esteller, Manel and Sardina, Jose L. and De La Torre, Carolina and Sigvardsson, Mikael and Vazquez, Berta N. and Vaquero, Alejandro}},
  issn         = {{1529-2908}},
  language     = {{eng}},
  number       = {{12}},
  pages        = {{2308--2319}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Immunology}},
  title        = {{A SIRT7-dependent acetylation switch regulates early B cell differentiation and lineage commitment through Pax5}},
  url          = {{http://dx.doi.org/10.1038/s41590-024-01995-7}},
  doi          = {{10.1038/s41590-024-01995-7}},
  volume       = {{25}},
  year         = {{2024}},
}