Acetylcholinesterase-R increases germ cell apoptosis but enhances sperm motility.
Changes in protein subdomains through alternative splicing often modify protein-protein interactions, altering biological processes. A relevant example is that of the stress-induced up-regulation of the acetylcholinesterase (AChE-R) splice variant, a common response in various tissues. In germ cells of male transgenic TgR mice, AChE-R excess associates with reduced sperm differentiation and sperm counts. To explore the mechanism(s) by which AChE-R up-regulation affects spermatogenesis, we identified AChE-R's protein partners through a yeast two-hybrid screen. In meiotic spermatocytes from TgR mice, we detected AChE-R interaction with the scaffold protein RACK1 and elevated apoptosis. This correlated with reduced scavenging by RACK1 of the pro-apoptotic TAp73, an outcome compatible with the increased apoptosis. In contrast, at later stages in sperm development, AChE-R's interaction with the glycolytic enzyme enolase-alpha elevates enolase activity. In transfected cells, enforced AChE-R excess increased glucose uptake and adenosine tri-phosphate (ATP) levels. Correspondingly, TgR sperm cells display elevated ATP levels, mitochondrial hyperactivity and increased motility. In human donors' sperm, we found direct association of sperm motility with AChE-R expression. Interchanging interactions with RACK1 and enolase-alpha may hence enable AChE-R to affect both sperm differentiation and function by participating in independent cellular pathways.
Mor
I
I
The Silberman Institute of Life Sciences, the Hebrew University of Jerusalem, Jerusalem, Israel.
Sklan
E H
EH
Podoly
E
E
Pick
M
M
Kirschner
M
M
Yogev
L
L
Bar-Sheshet Itach
S
S
Schreiber
L
L
Geyer
B
B
Mor
T
T
Grisaru
D
D
Soreq
H
H
D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001706:Biopsy; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D013081:Sperm Motility / Q000235:genetics; D013094:Spermatozoa / Q000166:cytology / Q000201:enzymology* / Q000502:physiology*; D013737:Testis / Q000166:cytology / Q000201:enzymology / Q000378:metabolism / Q000502:physiology / Q000601:surgery
D000110:Acetylcholinesterase