GLIPR1L1 is an IZUMO-binding protein required for optimal fertilization in the mouse

Abstract

BackgroundThe sperm protein IZUMO1 (Izumo sperm-egg fusion 1) and its recently identified binding partner on the oolemma, IZUMO1R, are among the first ligand-receptor pairs shown to be essential for gamete recognition and adhesion. However, the IZUMO1-IZUMO1R interaction does not appear to be directly responsible for promoting the fusion of the gamete membranes, suggesting that this critical phase of the fertilization cascade requires the concerted action of alternative fusogenic machinery. It has therefore been proposed that IZUMO1 may play a secondary role in the organization and/or stabilization of higher-order heteromeric complexes in spermatozoa that are required for membrane fusion.ResultsHere, we show that fertilization-competent (acrosome reacted) mouse spermatozoa harbor several high molecular weight protein complexes, a subset of which are readily able to adhere to solubilized oolemmal proteins. At least two of these complexes contain IZUMO1 in partnership with GLI pathogenesis-related 1 like 1 (GLIPR1L1). This interaction is associated with lipid rafts and is dynamically remodeled upon the induction of acrosomal exocytosis in preparation for sperm adhesion to the oolemma. Accordingly, the selective ablation of GLIPR1L1 leads to compromised sperm function characterized by a reduced ability to undergo the acrosome reaction and a failure of IZUMO1 redistribution.ConclusionsCollectively, this study characterizes multimeric protein complexes on the sperm surface and identifies GLIPRL1L1 as a physiologically relevant regulator of IZUMO1 function and the fertilization process.

Sperm chromatin integrity and DNA methylation in Norwegian Red bulls of contrasting fertility

“…These genes were zona pellucida binding protein ( ZPBP ) and regulated endocrine specific protein 18 ( RESP18 ) in hypermethylated group and glioma pathogenesis‐related 1‐like protein 1 ( GLIPR1L1 ) in hypomethylated group. Previous studies clearly demonstrated the significant role of GLIPR1L1 in sperm‐oocyte binding in mice and bovine (Caballero et al, 2012; Gaikwad et al, 2019; Gibbs et al, 2010). Furthermore, mice lacking ZPBP genes produced abnormal sperm cells with decreased ability to penetrate zona pellucida (Lin et al, 2007).…”

Unraveling Subcellular and Ultrastructural Changes During Vitrification of Human Spermatozoa: Effect of a Mitochondria-Targeted Antioxidant and a Permeable Cryoprotectant

“…In the present study, we detected IZUMO1, IZUMO2, and IZUMO4, and interestingly, the most important reported proteins responsible for fertilization were unaffected during the vitrification process, unlike with the slow-freezing method. Recently, GLIPR1-like protein 1 (GLIPRL1L1) was identified in the spermatozoa, and loss of this protein results in failure of IZUMO1 relocalization to fuse with eggs (Gaikwad et al, 2019). We also identified GLIPRL1L1 in human spermatozoa and found that the protein was unaffected during the vitrification process.…”

CRISPs Function to Boost Sperm Power Output and Motility

“…This, and the mismatch in the CRISP2 localization and null sperm phenotype data, suggests that other as yet unknown CRISP receptors exist on sperm. The identity of these receptors, and the possibility that CAP domain receptors may also exist on sperm, as indicated by the role of non-CRISP CAP proteins on sperm function ( Gaikwad et al, 2019 ), is the subject of ongoing research.…”

“…Several of these ion channels, including CatSper1 ( Vicens et al, 2014b ) and TRPM8 ( Majhi et al, 2015 ), have also experienced positive selection. In addition, the CAP domains, including those in CRISPs, are proposed to have roles in sperm-oocyte fusion ( Yamaguchi et al, 2011 ; Ernesto et al, 2015 ; Gaikwad et al, 2019 ). These data suggest that the recruitment of an ICR domain onto an ancestral CAP domain, and hinge region, during evolution to form the founding CRISP gene in vertebrates, then their subsequent expansion and over expression within the mammalian male reproductive tract ( Abraham and Chandler, 2017 ), represents an example of positive Darwinian evolution driven by the combined ability of CRISPs to boost sperm motility and assist in oocyte binding.…”