Hydrolytic and Nonenzymatic Functions of Acetylcholinesterase Comodulate Hemopoietic Stress Responses

Grisaru, Dan; Pick, Marjorie; Perry, Chava; Sklan, Ella H.; Almog, Ronit; Goldberg, Ilan; Naparstek, Elizabeth; Lessing, Joseph B.; Soreq, Hermona; Deutsch, Varda

doi:10.4049/jimmunol.176.1.27

Cited by 62 publications

(81 citation statements)

References 58 publications

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“…Under stress, AChE-S is substituted with AChE-R. 10 Consequent myelopoiesis could be solely due to AChE-R's capacity to upregulate hematopoiesis. 9 Alternatively, the decrease in AChE-S could also be actively involved, by avoiding negative regulatory function(s). To distinguish between these hypotheses, we used ASP 67 , the AChE-S C-terminal domain, as bait for a yeast two-hybrid screen.…”

Section: Resultsmentioning

confidence: 99%

“…Fluorescent detectors sensitivity, adjustment, isotype controls and analysis were all as detailed. 9,13 Antibodies used for flow cytometry are listed in Supplementary information.…”

Section: Flow Cytometric Acquisition and Analysismentioning

confidence: 99%

“…13 In situ hybridization and intracellular localization of AChE-S mRNA were performed as detailed. 9,18 AChE catalytic activity was determined as detailed. 11 Cell cultures K562 and human embryonic kidney (HEK) 293 cells were grown in RPMI and Dulbecco's modified Eagle's medium (DMEM, Biological Industries, Beit Ha'emek, Israel; Sigma, Jerusalem, Israel), both supplemented with 10% fetal calf serum (FCS) and 2 mM L-glutamine (Biological Industries) at 371C, in a humidified chamber with 5% CO 2 .…”

Section: Animalsmentioning

confidence: 99%

“…11 In hematopoietic cells, this induces myelopoiesis. 9 Also, transgenic mice overexpressing AChE-R display elevated lymphopoiesis and platelet counts. 12,13 Nevertheless, it remained unclear whether the gain of AChE-R function by itself suffices to induce the myelopoiesis and thrombocytosis that follow stress insults, or if the loss of AChE-S function(s) is also causally involved.…”

Section: Introductionmentioning

confidence: 99%

“…Multiple stress stimuli involve increased ratio between AChE-R and AChE-S in brain and blood cells alike. 9,10 AChE-R interacts with the intracellular scaffold protein RACK1 and its protein kinase C (PKC) partner through its C-terminal peptide, ARP. 11 In hematopoietic cells, this induces myelopoiesis.…”

Section: Introductionmentioning

confidence: 99%

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Acetylcholinesterase/C terminal binding protein interactions modify Ikaros functions, causing T lymphopenia

et al. 2007

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Hematological changes induced by various stress stimuli are accompanied by replacement of the primary acetylcholinesterase (AChE) 3 0 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 0 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.

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Section: Resultsmentioning

confidence: 99%

“…Fluorescent detectors sensitivity, adjustment, isotype controls and analysis were all as detailed. 9,13 Antibodies used for flow cytometry are listed in Supplementary information.…”

Section: Flow Cytometric Acquisition and Analysismentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acetylcholinesterase/C terminal binding protein interactions modify Ikaros functions, causing T lymphopenia

et al. 2007

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New paradigms in the study of the cholinergic system and metabolic diseases: Acetyl‐and‐butyrylcholinesterase

Villeda‐González,

Gómez‐Olivares,

Baiza‐Gutman

2024

Journal Cellular Physiology

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Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are enzymes that belong to the neuromuscular cholinergic system, their main function is to hydrolyze the neurotransmitter acetylcholine (ACh), through their hydrolysis these enzymes regulate the neuronal and neuromuscular cholinergic system. They have recently attracted considerable attention due to the discovery of new enzymatic and nonenzymatic functions. These discoveries have aroused the interest of numerous scientists, consolidating the relevance of this group of enzymes. Recent investigations have revealed a positive correlation between several risk factors for metabolic syndrome (MetS) and the expression of cholinesterases (ChE's), which underscore the impact of high ChE's activity on the pro‐inflammatory state associated with MetS. In addition, the excessive hydrolysis of ACh and other choline esters (succinylcholine, propionylcholine, butyrylcholine, etc.) by both ChE's results in the overproduction of fatty acid precursor metabolites, which facilitate the synthesis of very low‐density lipoproteins and triacylglycerols. Participation in these processes may represent the link between ChE's and metabolic disorders. However, further scientific research is required to fully elucidate the involvement of ChE's in metabolic diseases. This review aims to collect recent research studies that contribute to understanding the association between the cholinergic system and metabolic diseases.

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Cholinergic status modulations in human volunteers under acute inflammation

et al. 2007

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Cholinergic Status, the total soluble circulation capacity for acetylcholine hydrolysis, was tested for putative involvement in individual variabilities of the recruitment of immune cells in response to endotoxin challenge. Young (average age 26) and elderly (average age 70) volunteers injected with either Escherichia coli endotoxin or saline on two different occasions were first designated Enhancers and Suppressors if they showed increase or decrease, respectively, in plasma acetylcholinesterase (AChE) activity 1.5 h after endotoxin administration compared to saline. Enhancers showed significant co-increases in plasma butyrylcholinesterase (BChE) and paraoxonase (PON1) activities, accompanied by rapid recovery of lymphocyte counts. Young Enhancers alone showed pronounced post-exposure increases in the pro-inflammatory cytokine interleukin-6 (IL-6), and upregulation of the normally rare, stress-induced AChE-R variant, suggesting age-associated exhaustion of the cholinergic effects on recruiting innate immune reactions to endotoxin challenge. Importantly, IL-6 injected to young volunteers or administered in vitro to primary mononuclear blood cells caused upregulation of AChE, but not BChE or PON1, excluding it from being the sole cause for this extended response. Interestingly, Suppressors but not Enhancers showed improved post-exposure working memory performance, indicating that limited cholinergic reactions may be beneficial for cognition. Our findings establish Cholinergic Status modulations as early facilitators and predictors of individual variabilities in the peripheral response to infection.

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Hydrolytic and Nonenzymatic Functions of Acetylcholinesterase Comodulate Hemopoietic Stress Responses

Cited by 62 publications

References 58 publications

Acetylcholinesterase/C terminal binding protein interactions modify Ikaros functions, causing T lymphopenia

Acetylcholinesterase/C terminal binding protein interactions modify Ikaros functions, causing T lymphopenia

New paradigms in the study of the cholinergic system and metabolic diseases: Acetyl‐and‐butyrylcholinesterase

Cholinergic status modulations in human volunteers under acute inflammation

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