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A SIRT7-dependent acetylation switch regulates early B cell differentiation and lineage commitment through Pax5
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A SIRT7-dependent acetylation switch regulates early B cell differentiation and lineage commitment through Pax5
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Journal Article
A SIRT7-dependent acetylation switch regulates early B cell differentiation and lineage commitment through Pax5
2024
Overview
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
−/−
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.
Gámez-García et al. show that the deacetylase SIRT7 modulates the acetylation of Pax5 and its ability to repress alternate lineage programs and promote B cell differentiation and commitment in B cell progenitor cells.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Acute lymphoblastic leukemia
/ Animals
/ Biomedical and Life Sciences
/ Humans
/ Immunologi inom det medicinska området (Här ingår: Cell- och immunterapi)
/ Immunology in the Medical Area (including Cell and Immunotherapy)
/ Leukemia
/ Medicinska och farmaceutiska grundvetenskaper
/ Mice
/ PAX5 Transcription Factor - genetics
/ PAX5 Transcription Factor - metabolism
/ Sirtuins
