SPINK3-sperm interaction determines a stable sperm subpopulation with intact CatSper channel
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Sperm capacitation involves proteolytic remodeling of membrane proteins, including components of the CatSper calcium channel, which is essential for hyperactivation and male fertility. Here, we identify the seminal protease inhibitor SPINK3, a known decapacitation factor that suppresses premature capacitation in the female tract, as the first physiological inhibitor of CATSPER1 processing. In mouse sperm, SPINK3 blocks capacitation-induced CATSPER1 cleavage, preserving a subpopulation with intact CatSper channels and lacking pTyr development in the flagellum. SPINK3 localizes to the outer surface of the sperm principal piece membrane in a CatSper-dependent but non-quadrilateral pattern, stabilizes membrane organization, and delays cholesterol efflux. These results reveal SPINK3 as a multifunctional regulator of capacitation, shaping sperm subpopulations in the female reproductive tract.
SIGNIFICANCE STATEMENT
This study unveils a novel physiological regulator from the male reproductive tract, SPINK3, which extracellularly controls the processing of CATSPER1, a key subunit of the CatSper calcium channel essential for sperm capacitation in mice. We show that SPINK3 binds to the sperm surface and prevents the processing of CATSPER1 during capacitation. SPINK3-sperm interaction is dependent on the presence of the sperm-specific CatSper channel. Our findings reveal that SPINK3 stabilizes sperm membranes providing new insights into the molecular regulation of sperm function and fertility.
