2. Academic Validation
  3. Role of Caspase-10-P13tBID axis in erythropoiesis regulation

Role of Caspase-10-P13tBID axis in erythropoiesis regulation

  • Cell Death Differ. 2023 Jan;30(1):208-220. doi: 10.1038/s41418-022-01066-0.
Mathilde Lamarque # 1 2,  Emilie-Fleur Gautier # 2 3,  François Rodrigues 1 2,  Flavia Guillem 1 2,  Elisa Bayard 1 2,  Cédric Broussard 4,  Thiago Maciel Trovati 1 2,  Jean-Benoît Arlet 5,  Patrick Mayeux 2 3,  Olivier Hermine 6 7 8,  Geneviève Courtois 9 10
Affiliations

Affiliations

  • 1 INSERM U1163, Institut Imagine, Université Paris-Cité, Paris, France.
  • 2 Laboratory of Excellence GR-Ex, Paris, France.
  • 3 Institut Cochin, Département Développement, Reproduction, Cancer, CNRS INSERM UMR, 8104, Paris, France.
  • 4 3P5 Proteom'IC facility, Université Paris-Cité, CNRS, INSERM, Institut Cochin, F-75014, Paris, France.
  • 5 Service de Médecine Interne, Hôpital européen Georges-Pompidou APHP, Faculté de Médecine Paris Descartes, Université Paris-Cité, Paris, France.
  • 6 INSERM U1163, Institut Imagine, Université Paris-Cité, Paris, France. [email protected].
  • 7 Laboratory of Excellence GR-Ex, Paris, France. [email protected].
  • 8 Department of Hematology, Hôpital Necker Enfants Malades, AP-HP, Faculté de Médecine Paris Descartes, Université Paris-Cité, Paris, France. [email protected].
  • 9 INSERM U1163, Institut Imagine, Université Paris-Cité, Paris, France. [email protected].
  • 10 Laboratory of Excellence GR-Ex, Paris, France. [email protected].
  • # Contributed equally.
PMID: 36202990 DOI: 10.1038/s41418-022-01066-0
Abstract

Red blood cell production is negatively controlled by the rate of Apoptosis at the stage of CFU-E/pro-erythroblast differentiation, depending on the balance between erythropoietin (EPO) levels and activation of the Fas/FasL pathway. At this stage, activation of transient caspases through depolarization via mitochondrial outer membrane permeabilization (MOMP) is also required for terminal erythroid differentiation. Molecular mechanisms regulating the differential levels of MOMP during differentiation and Apoptosis, however, remain poorly understood. Here we show a novel and essential role for the caspase-10-P13-tBID axis in erythroid terminal differentiation. Caspase-10 (but not Caspase-8, which is activated during Apoptosis) is activated at the early stages of erythroid terminal differentiation leading to the cleavage of P22-BID into P18-tBID, and later into P13-tBID. Erythropoietin (EPO) by inducing Casein Kinase I alpha (CKIα) expression, which in turn phosphorylates P18-tBID, prevents the generation of MYR-P15-tBID (leading to Apoptosis) and allows the generation of P13-tBID by Caspase-10. Unlike P15-tBID, P13-tBID is not myristoylated and as such, does not irreversibly anchor the mitochondrial membrane resulting in a transient MOMP. Likewise, transduction of a P13-tBID fragment induces rapid and strong erythroid terminal differentiation. Thus, EPO modulates the pattern of BID cleavage to control the level of MOMP and determines the fate of erythroblasts between Apoptosis and differentiation. This pathway is impaired in 5q- myelodysplastic syndromes because of CK1α haplo-insufficiency and may contribute to erythroid differentiation arrest and high sensitivity of this disease to lenalidomide (LEN).

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