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

Abstract

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.

Identification and Validation of Yak (Bos grunniens) Frozen–Thawed Sperm Proteins Associated with Capacitation and the Acrosome Reaction

“…PPARγ can control this process via glucose metabolic activity and other pathways, enhancing capacitated sperm motility and thus serving as an important intermediary between metabolic activity and male fertility. − Chen et al observed PPARγ and cAMP to synergistically regulate gene expression, and others have found the activation of PPARγ to influence the cAMP-mediated signaling pathway through mechanisms linked to the regulation of PKA. , The activation of PPARγ can also reportedly regulate components of the PI3K signaling cascade in several cell types, fully activating the major downstream gene AKT in the PI3K signal transducer . GSEA data from this study revealed that CAP sperm exhibited the significant downregulation of the PI3K-Akt signaling pathway gene set, in line with prior studies demonstrating that PI3K-Akt-dependent actin polymerization in the sperm tail necessitates both PKA and protein Tyr-P modification in the context of sperm capacitation. , Sperm tail PI3K-Akt signaling enhancement has also been linked to enhanced motility and survival in the context of capacitation, while in the sperm head such signaling can suppress cAMP surges and premature AR induction. ,, …”

“…75,76 Sperm tail PI3K-Akt signaling enhancement has also been linked to enhanced motility and survival in the context of capacitation, while in the sperm head such signaling can suppress cAMP surges and premature AR induction. 75,77,78 Fatty acid-binding protein 3 (FABP3) functions to promote fatty acid uptake and intracellular transport such that these macromolecules can undergo appropriate metabolic processing, thereby regulating gene expression and associated cell growth activity. 79 Dynamic shifts in sperm fatty acid composition are linked to fertilizing ability, and FABPs may play a role in regulating this process.…”

“…71 GSEA data from this study revealed that CAP sperm exhibited the significant downregulation of the PI3K-Akt signaling pathway gene set, in line with prior studies demonstrating that PI3K-Akt-dependent actin polymerization in the sperm tail necessitates both PKA and protein Tyr-P modification in the context of sperm capacitation. 75,76 Sperm tail PI3K-Akt signaling enhancement has also been linked to enhanced motility and survival in the context of capacitation, while in the sperm head such signaling can suppress cAMP surges and premature AR induction. 75,77,78 Fatty acid-binding protein 3 (FABP3) functions to promote fatty acid uptake and intracellular transport such that these macromolecules can undergo appropriate metabolic processing, thereby regulating gene expression and associated cell growth activity.…”

Small-molecule targeting of GPCR-independent non-canonical G protein signaling inhibits cancer progression

“…In this work we identify and characterize a chemical probe of broad utility for dissecting atypical mechanisms of cellular communication mediated by G-proteins with important biomedical implications not only for cancer, but also for fibrosis, and male fertility, among other maladies (8, 9, 17, 18, 20, 40, 41). Because its chemical scaffold is synthetically tractable, IGGi-11 may further serve as a lead compound to develop analogs with improved potency and pharmacokinetic properties that could have therapeutic value.…”

“…In this work we identify and characterize a chemical probe of broad utility for dissecting atypical mechanisms of cellular communication mediated by G-proteins with important biomedical implications not only for cancer, but also for fibrosis, and male fertility, among other maladies (8,9,17,18,20,40,41).…”