Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, San Diego, United States
Gajanan Dattatray Katkar
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, San Diego, United States
Inmaculada Lopez-Sanchez
Department of Medicine, School of Medicine, University of California San Diego, San Diego, United States
Sahar Taheri
Department of Computer Science and Engineering, Jacob’s School of Engineering, University of California San Diego, San Diego, United States
Celia Espinoza
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, San Diego, United States
Cristina Rohena
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, San Diego, United States
Debashis Sahoo
Department of Computer Science and Engineering, Jacob’s School of Engineering, University of California San Diego, San Diego, United States; Moore’s Comprehensive Cancer Center, University of California San Diego, San Diego, United States; Department of Pediatrics, School of Medicine, University of California San Diego, San Diego, United States
Department of Cellular and Molecular Medicine, School of Medicine, University of California San Diego, San Diego, United States; Department of Medicine, School of Medicine, University of California San Diego, San Diego, United States; Moore’s Comprehensive Cancer Center, University of California San Diego, San Diego, United States; Veterans Affairs Medical Center, Washington DC, United States
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.
