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

Sequoyah Reynoso | Vanessa Castillo | Gajanan Dattatray Katkar | Inmaculada Lopez-Sanchez | Sahar Taheri | Celia Espinoza | Cristina Rohena | Debashis Sahoo | Pascal Gagneux | Pradipta Ghosh
eLife | 2021

For 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 conditional knockout (cKO) 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.

Pubmed ID: 34409938

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: T32 CA121938
  • Agency: NIAID NIH HHS, United States
    Id: R21 AI129894
  • Agency: NCI NIH HHS, United States
    Id: R01 CA100768
  • Agency: NCI NIH HHS, United States
    Id: R01 CA160911
  • Agency: NIDDK NIH HHS, United States
    Id: T32 DK007202
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM138385
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM095882
  • Agency: NCI NIH HHS, United States
    Id: R01 CA238042
  • Agency: NIDDK NIH HHS, United States
    Id: R01 DK099226
  • Agency: NIH HHS, United States
    Id: S10 OD026929
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI141630

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