Inositol 1,3,4,5-tetrakisphosphate controls proapoptotic Bim gene expression and survival in B cells.
The contribution of the B isoform of inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] 3-kinase (or Itpkb) and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P(4)], its reaction product, to B cell function and development remains unknown. Here, we show that mice deficient in Itpkb have defects in B cell survival leading to specific and intrinsic developmental alterations in the B cell lineage and antigen unresponsiveness in vivo. The decreased B cell survival is associated with a decreased phosphorylation of Erk1/2 and increased Bim gene expression. B cell survival, development, and antigen responsiveness are normalized in parallel to reduced expression of Bim in Itpkb(-/-) Bim(+/-) mice. Analysis of the signaling pathway downstream of Itpkb revealed that Ins(1,3,4,5)P(4) regulates subcellular distribution of Rasa3, a Ras GTPase-activating protein acting as an Ins(1,3,4,5)P(4) receptor. Together, our results indicate that Itpkb and Ins(1,3,4,5)P(4) mediate a survival signal in B cells via a Rasa3-Erk signaling pathway controlling proapoptotic Bim gene expression.
Maréchal
Yoann
Y
Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Faculté de Médecine, Université Libre de Bruxelles, Rue des Professeurs Jeener et Brachet 12, 6041 Gosselies, Belgium.
Pesesse
Xavier
X
Jia
Yonghui
Y
Pouillon
Valérie
V
Pérez-Morga
David
D
Daniel
Julien
J
Izui
Shozo
S
Cullen
Peter J
PJ
Leo
Oberdan
O
Luo
Hongbo R
HR
Erneux
Christophe
C
Schurmans
Stéphane
S
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics*; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000502:physiology*; D000072224:Bcl-2-Like Protein 11; D001853:Bone Marrow / Q000276:immunology; D002470:Cell Survival; D005786:Gene Expression Regulation; D007072:Immunoglobulin D / Q000032:analysis; D007075:Immunoglobulin M / Q000032:analysis; D007295:Inositol Phosphates / Q000494:pharmacology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D007295:Inositol Phosphates; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; C081655:inositol-1,3,4,5-tetrakisphosphate; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase
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