PUBLICATION

ZAKα/P38 kinase signaling pathway regulates hematopoiesis by activating the NLRP1 inflammasome

Authors
Rodríguez-Ruiz, L., Lozano-Gil, J.M., Naranjo-Sánchez, E., Martínez-Balsalobre, E., Martínez-López, A., Lachaud, C., Blanquer, M., Phung, T.K., García-Moreno, D., Cayuela, M.L., Tyrkalska, S.D., Pérez-Oliva, A.B., Mulero, V.
ID
ZDB-PUB-230908-51
Date
2023
Source
EMBO Molecular Medicine   15(10): e18142 (Journal)
Registered Authors
Mulero, Victor
Keywords
HSPCs, anemia, inflammation, neutrophilia, zebrafish
MeSH Terms
none
PubMed
37675820 Full text @ EMBO Mol. Med.
Abstract
Chronic inflammatory diseases are associated with hematopoietic lineage bias, including neutrophilia and anemia. We have recently identified that the canonical inflammasome mediates the cleavage of the master erythroid transcription factor GATA1 in hematopoietic stem and progenitor cells (HSPCs). We report here that genetic inhibition of Nlrp1 resulted in reduced number of neutrophils and increased erythrocyte counts in zebrafish larvae. We also found that the NLRP1 inflammasome in human cells was inhibited by LRRFIP1 and FLII, independently of DPP9, and both inhibitors regulated hematopoiesis. Mechanistically, erythroid differentiation resulted in ribosomal stress-induced activation of the ZAKα/P38 kinase axis which, in turn, phosphorylated and promoted the assembly of NLRP1 in both zebrafish and human. Finally, inhibition of Zaka with the FDA/EMA-approved drug Nilotinib alleviated neutrophilia in a zebrafish model of neutrophilic inflammation and promoted erythroid differentiation and GATA1 accumulation in K562 cells. In conclusion, our results reveal that the NLRP1 inflammasome regulates hematopoiesis and pave the way to develop novel therapeutic strategies for the treatment of hematopoietic alterations associated with chronic inflammatory and rare diseases.
Genes / Markers
Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a9
    		Complex
    c264TgTransgenic Insertion
      hi2217TgTransgenic Insertion
      i114TgTransgenic Insertion
        nz50TgTransgenic Insertion
          sd2TgTransgenic Insertion
            utn6TgTransgenic Insertion
              w2
                		Point Mutation
                xt2TgTransgenic Insertion
                  1 - 9 of 9
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  Target Reagent Reagent Type
                  fliiCRISPR4-fliiCRISPR
                  lrrfip1aCRISPR3-lrrfip1aCRISPR
                  lrrfip1bCRISPR1-lrrfip1bCRISPR
                  map3k20aCRISPR5-map3k20aCRISPR
                  map3k20bCRISPR2-map3k20bCRISPR
                  nlrp1CRISPR1-nlrp1CRISPR
                  1 - 6 of 6
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                  Fish
                  No data available
                  Antibodies
                  Orthology
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  DsRedEFGDsRed
                  DsRed2EFGDsRed2
                  GAL4EFGGAL4
                  GFPEFGGFP
                  LanYFPEFGLanYFP
                  mCherryEFGmCherry
                  NTREFGNTR
                  1 - 7 of 7
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                  Mapping
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                  Citation
                  Rodríguez-Ruiz, L., Lozano-Gil, J.M., Naranjo-Sánchez, E., Martínez-Balsalobre, E., Martínez-López, A., Lachaud, C., Blanquer, M., Phung, T.K., García-Moreno, D., Cayuela, M.L., Tyrkalska, S.D., Pérez-Oliva, A.B., Mulero, V. (2023) ZAKα/P38 kinase signaling pathway regulates hematopoiesis by activating the NLRP1 inflammasome. EMBO Molecular Medicine. 15(10):e18142.