Acetylcholinesterase/C terminal binding protein interactions modify Ikaros functions, causing T lymphopenia.
Hematological changes induced by various stress stimuli are accompanied by replacement of the primary acetylcholinesterase (AChE) 3' splice variant acetylcholinesterase-S (AChE-S) with the myelopoietic acetylcholinesterase-R (AChE-R) variant. To search for putative acetylcholinesterase-S interactions with hematopoietic pathways, we employed a yeast two-hybrid screen. The transcriptional co-repressor C-terminal binding protein (CtBP) was identified as a protein partner of the AChE-S C terminus. In erythroleukemic K562 cells, AChE-S displayed nuclear colocalization and physical interaction with CtBP. Furthermore, co-transfected AChE-S reduced the co-repressive effect of CtBP over the hematopoietic transcription factor, Ikaros. In transgenic mice, overexpressed human (h) AChE-S mRNA induced selective bone marrow upregulation of Ikaros while suppressing FOG, another transcriptional partner of CtBP. Transgenic bone marrow cells showed a correspondingly elevated potential for producing progenitor colonies, compared with controls, while peripheral blood showed increased erythrocyte counts as opposed to reduced platelets, granulocytes and T lymphocytes. AChE's 3' alternative splicing, and the corresponding changes in AChE-S/CtBP interactions, thus emerge as being actively involved in controlling hematopoiesis and the potential for modulating immune functions, supporting reports on malfunctioning immune reactions under impaired splice site selection.
Perry
C
C
Department of Hematology and Bone Marrow Transplantation, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Pick
M
M
Podoly
E
E
Gilboa-Geffen
A
A
Zimmerman
G
G
Sklan
E H
EH
Ben-Shaul
Y
Y
Diamant
S
S
Soreq
H
H
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000429:Alcohol Oxidoreductases / Q000378:metabolism* / Q000502:physiology; D017398:Alternative Splicing / Q000502:physiology; D000818:Animals; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D051740:Ikaros Transcription Factor / Q000502:physiology*; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology; D008231:Lymphopenia / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding; D013601:T-Lymphocytes
D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; D007527:Isoenzymes; D051740:Ikaros Transcription Factor; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D000110:Acetylcholinesterase