GIV/Girdin, a non-receptor modulator for Gαi/s, regulates spatiotemporal signaling during sperm capacitation and is required for male fertility

Autor: Inmaculada Lopez-Sanchez, Sahar Taheri, Vanessa Castillo, Pradipta Ghosh, Gajanan D. Katkar, Cristina C. Rohena, Sequoyah Reynoso, Pascal Gagneux, Debashis Sahoo, Celia R. Espinoza
Rok vydání: 2021
Předmět:
Male
Mouse
Vesicular Transport Proteins
GTPase
Reproductive health and childbirth
male fertility
Mice
Spermatocytes
Conditional gene knockout
Testis
cell biology
Biology (General)
Tyrosine
Phosphorylation
Receptor modulator
Sperm motility
Girdin
Mice
Knockout
Chemistry
General Neuroscience
Microfilament Proteins
General Medicine
Cell biology
Medicine
Female
Research Article
Human
Proto-oncogene tyrosine-protein kinase Src
Signal Transduction
QH301-705.5
Science
Knockout
Gi alpha subunit
Motility
Down-Regulation
Semen
Biology
General Biochemistry
Genetics and Molecular Biology
developmental biology
Capacitation
spermatozoa
cAMP
Animals
Humans
human
mouse
General Immunology and Microbiology
Contraception/Reproduction
Cell Biology
Sperm
Fertility
Gene Expression Regulation
Infertility
Biochemistry and Cell Biology
Sperm Capacitation
Developmental Biology
Zdroj: eLife, Vol 10 (2021)
eLife
Popis: SUMMARYFor a sperm to successfully fertilize an egg, it must first undergo capacitation in the female reproductive tract, and later undergo acrosomal reaction (AR) upon encountering an egg surrounded by its vestment. How premature AR is avoided despite rapid surges in signaling cascades during capacitation remains unknown. Using a combination of KO mice and cell-penetrating peptides, we show that GIV (CCDC88A), a guanine nucleotide-exchange modulator (GEM) for trimeric GTPases, is highly expressed in spermatocytes and is required for male fertility. GIV is rapidly phosphoregulated on key tyrosine and serine residues in human and murine spermatozoa. These phosphomodifications enable GIV-GEM to orchestrate two distinct compartmentalized signaling programs in the sperm tail and head; in the tail, GIV enhances PI3K→ Akt signals, sperm motility and survival, whereas in the head it inhibits cAMP surge and premature AR. Furthermore, GIV transcripts are downregulated in the testis and semen of infertile men. These findings exemplify the spatiotemporally segregated signaling programs that support sperm capacitation and shed light on a hitherto unforeseen cause of infertility in men.GRAPHIC ABSTRACTHIGHLIGHTSGIV is highly expressed in spermatozoa, and is required for male fertilityGIV is rapidly phosphoregulated during sperm capacitationIt enhances tyrosine-based signals in sperm tail, enhances motilityIt suppresses cAMP in the sperm head, inhibits premature acrosome exocytosis
Databáze: OpenAIRE
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