IKBA phosphorylation governs human sperm motility through ACC-mediated fatty acid beta-oxidation

Abstract

The nuclear factor-κB (NF-κB) signaling pathway regulates specific immunological responses and controls a wide range of physiological processes. NF-κB inhibitor alpha (IKBA) is an NF-κB inhibitory mediator in the cytoplasm that modulates the nuclear translocation and DNA binding activities of NF-κB proteins. However, whether the upstream cascade of the canonical NF-κB signaling pathway has physiological roles independent of IKBA-mediated transcriptional activation remains unclear. Herein we investigated the function of IKBA in mature sperm in which transcriptional and translational events do not occur. IKBA was highly expressed in human sperm. The repression of IKBA phosphorylation by its inhibitor Bay117082 markedly enhanced sperm motility. On the contrary, lipopolysaccharide-stimulated IKBA phosphorylation significantly decreased sperm motility. Nevertheless, Bay117082 treatment did not affect the motility of IKBA-knockout sperm. Further, untargeted metabolomic analysis and pharmacological blocking assays revealed that the Bay117082-induced increase in sperm motility was attributable to fatty acid β-oxidation (FAO) enhancement. In addition, we found that IKBA phosphorylation inhibition resulted in a significant reduction of acetyl-CoA carboxylase levels in the FAO metabolic pathway. Our findings indicate that IKBA-mediated signaling orchestrates sperm motility program and improves our understanding of transcription-independent NF-κB signaling pathway in cells.

Aquaporin-7-Mediated Glycerol Permeability Is Linked to Human Sperm Motility in Asthenozoospermia and during Sperm Capacitation

“…Sperm cells have been found to express the machinery necessary for the fatty acid β-oxidation [33]. Further studies also point to a significant role of the fatty acid β-oxidation on ATP production and sperm motility [34][35][36]. However, the linkage between sperm aquaglyceroporin expression and lipid or fatty acid metabolism still eludes the scientific community, but is certainly something worth exploring.…”

Genetic analysis and characterization of reproductive control genes in Belgian and Qinchuan cattle population structure

“…The NFKBIA gene encodes a member of the NF-κB inhibitor family, which contains multiple anchor protein repeat structural domains. Inhibition of IKBA phosphorylation signi cantly enhances sperm motility [20]. Mutations in the NFKBIA gene result in bracketed ectodermal dysplasia [21] So the expression of NFKBIA gene may affect the reproductive performance of the population (Fig.…”