Cysteine-Rich Secretory Proteins (CRISP) are Key Players in Mammalian Fertilization and Fertility

Abstract

Mammalian fertilization is a complex process involving a series of successive sperm-egg interaction steps mediated by different molecules and mechanisms. Studies carried out during the past 30 years, using a group of proteins named CRISP (Cysteine-RIch Secretory Proteins), have significantly contributed to elucidating the molecular mechanisms underlying mammalian gamete interaction. The CRISP family is composed of four members (i.e., CRISP1-4) in mammals, mainly expressed in the male tract, present in spermatozoa and exhibiting Ca2+ channel regulatory abilities. Biochemical, molecular and genetic approaches show that each CRISP protein participates in more than one stage of gamete interaction (i.e., cumulus penetration, sperm-ZP binding, ZP penetration, gamete fusion) by either ligand-receptor interactions or the regulation of several capacitation-associated events (i.e., protein tyrosine phosphorylation, acrosome reaction, hyperactivation, etc.) likely through their ability to regulate different sperm ion channels. Moreover, deletion of different numbers and combination of Crisp genes leading to the generation of single, double, triple and quadruple knockout mice showed that CRISP proteins are essential for male fertility and are involved not only in gamete interaction but also in previous and subsequent steps such as sperm transport within the female tract and early embryo development. Collectively, these observations reveal that CRISP have evolved to perform redundant as well as specialized functions and are organized in functional modules within the family that work through independent pathways and contribute distinctly to fertility success. Redundancy and compensation mechanisms within protein families are particularly important for spermatozoa which are transcriptionally and translationally inactive cells carrying numerous protein families, emphasizing the importance of generating multiple knockout models to unmask the true functional relevance of family proteins. Considering the high sequence and functional homology between rodent and human CRISP proteins, these observations will contribute to a better understanding and diagnosis of human infertility as well as the development of new contraceptive options.

Fertilization of Ascidians: Gamete Interaction, Self/Nonself Recognition and Sperm Penetration of Egg Coat

“…CiUrabin belongs to a cysteine-rich secretory protein (CRISP) family containing a pathogenesis-related (PR) domain and a glycosylphosphatidylinositol (GPI)-anchor attachment site ( Yamaguchi et al, 2011 ). Sperm CRISP family proteins participate in several steps in mammalian fertilization ( Gonzalez et al, 2021 ). In particular, the PR domain of CRISP-1 is evolutionarily conserved and involved in sperm-egg binding ( Ellerman et al, 2006 ).…”

Egg cell‐secreted aspartic proteases ECS1/2 promote gamete attachment to prioritize the fertilization of egg cells over central cells in Arabidopsis

“…For instance, sperm‐expressed members of the A DISINTEGRIN AND A METALLOPROTEASE DOMAIN (ADAM) family of metalloproteases (adamalysins) have multiple functions in sperm migration through the oviduct and zona, as well as in oolemma adhesion (Gahlay and Rajput, 2020). The disintegrin domain of ADAMs interacts with egg‐expressed integrins and Cysteine‐rich Secretory Proteins (CRISPs) to possibly regulate the attachment of the sperm to the oocyte (Eto et al, 2002; Desiderio et al, 2010; Gonzalez et al, 2021), while the metalloprotease domain is involved in degradation and remodeling of the extracellular matrix to facilitate cell–cell adhesion (D'Occhio et al, 2020). A lysozyme‐like acrosomal protein, SPERM ACROSOME MEMBRANE‐ASSOCIATED 3 (SPACA3/SLLP1), which is relocated to the equatorial segment after the acrosome reaction is activated, works together with a specific oolemma metalloprotease SPERM ACROSOMAL SLLP1 BINDING (SAS1B) to control sperm‐egg adhesion and fusion (Herrero et al, 2005; Sachdev et al, 2012).…”

The vertebrate- and testis- specific transmembrane protein C11ORF94 plays a critical role in sperm-oocyte membrane binding

“…CRISPs family is composed of four members (CRISP1-4) in mammals. It is mainly expressed in the male reproductive tract, exists in sperm, and shows the ability of calcium channel regulation [51]. IVF experiments showed that Crisp1 deficiency can destroy the fertilization ability of sperm using ZP-free oocytes, where the percentage of oocyte binding-fusion is significantly inhibited in a concentration dependent manner [52,53].…”