GIV/Girdin, a Non-receptor Modulator for Gαi/s, Regulates Spatiotemporal Signaling during Sperm Capacitation and is Required for Male Fertility

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 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 ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/442927v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@f4901forg.highwire.dtl.DTLVardef@2211dforg.highwire.dtl.DTLVardef@c37ff5org.highwire.dtl.DTLVardef@105eed7_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIGIV is highly expressed in spermatozoa, and is required for male fertility C_LIO_LIGIV is rapidly phosphoregulated during sperm capacitation C_LIO_LIIt enhances tyrosine-based signals in sperm tail, enhances motility C_LIO_LIIt suppresses cAMP in the sperm head, inhibits premature acrosome exocytosis C_LI