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.
Highlights
The sperm protein Izumo sperm-egg fusion protein 1 (IZUMO1) (Izumo sperm-egg fusion 1) and its recently identified binding partner on the oolemma, IZUMO1 receptor (IZUMO1R), are among the first ligand-receptor pairs shown to be essential for gamete recognition and adhesion
Mass spectrometry analysis of the predominant oolemma protein binding band at ~ 750 kDa identified several peptides corresponding to IZUMO1 and GLIPR1L1 (Table 1)
Consistent with our previous work [21], under reducing conditions, the GLIPR1L1 antibody bound to a predominant band with a molecular weight of 37 kDa, while the IZUMO1 antibody bound to a protein with a mass of ~ 56 kDa (Fig. 1b)
Summary
The 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. Such findings are seemingly at odds with the demonstration that sperm from Izumo null males are capable of binding to but not fusing with the oolemma [3] These apparently contradictory results may be reconciled by the existence of alternative IZUMO1 receptor(s) that mediate gamete membrane fusion [7] or by the propensity of IZUMO1 to associate with other, as yet unidentified sperm surface proteins, leading to the formation of several higher-order multiprotein complexes [11]. It is widely accepted that a majority of enveloped viruses use protein complexes to regulate their progression through the sequential phases of fusion with a suitable target cell membrane, i.e., receptor recognition, triggering of fusion, and fusion execution [13, 14]. The complexity of this membrane fusion machinery ranges from the use of multiple copies of a single glycoprotein for the entire fusion reaction [15], through to the segregation of the activities responsible for membrane attachment and membrane fusion into different proteins and separate multimeric complexes [16]
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