A novel posttranslational modification of histone, H3 S-sulfhydration, is down-regulated in asthenozoospermic sperm

Abstract

Oxidative stress is one of the major causes leading to male infertility including asthenozoospermia. Hydrogen sulfide (H2S) has been widely recognized to be a potent antioxidant whose role is partially implemented by protein S-sulfhydration. However, protein S-sulfhydration has not been reported in germ cells. Therefore, we investigated whether asthenozoospermia could be associated with sperm protein S-sulfhydration. S-sulfhydrated proteins in human sperm were enriched via biotin-switch assay and analyzed using LC-MS/MS spectrometry. Two hundred forty-four S-sulfhydrated proteins were identified. Importantly, we validated that sperm histones H3.1 and H3.3 were the S-sulfhydrated proteins. Their S-sulfhydrated amino acid residue was Cysteine111. Abundances of S-sulfhydrated H3 (sH3) and S-sulfhydrated H3.3 (sH3.3) were significantly down-regulated in asthenozoospermic sperm, compared with the fertile controls, and were significantly correlated with progressive motility. Retinoic acid (RA) up-regulated level of sH3.3 in primary round spermatids and the C18-4 cells (a mouse spermatogonial stem cell line). Overexpression of the mutant H3.3 (Cysteine111 was replaced with serine) affected expression of 759 genes and raised growth rate of C18-4 cells. For the first time, S-sulfhydration H3 and H3.3 were demonstrated in the present study. Our results highlight that aberrant S-sulfhydration of H3 is a new pathophysiological basis in male infertility.

Supplementation of sperm cryopreservation media with H2S donors enhances sperm quality, reduces oxidative stress, and improves in vitro fertilization outcomes

“…In this regard, a series of studies have demonstrated that H 2 S has important physiological and cytoprotective functions in the biological systems 39 , 40 . Some studies have revealed some mechanisms for the regulatory effect of H 2 S on ROS production in biological systems.…”

Sperm Phosphoproteome: Unraveling Male Infertility

“…In this regard, it is necessary to focus our attention on sperm motile capacity, and the abnormal content or presence of PTMs, such as the reduced abundance of lysine glutarylation in several proteins located in the tail of human spermatozoa, just as a diminished quantity of S-sulfhydrated H3 and H3.3 histones positively correlate with sperm progressive motility [12,13]; conversely the level of SUMO1-positive spermatozoa and the quantity of lysine 2-hydroxyisobutyrylation in sperm proteins trend towards higher grades in asthenozoospermic men compared with normozoospermic ones, indicating a negative association with the motility of human spermatozoa in this case [14,15]. Additionally, lysine acetylation seems to be essential for human sperm motility and fertilization [16].…”