C11orf94/Frey is a key regulator for male fertility by controlling Izumo1 complex assembly

Abstract

Although gamete fusion represents the central event in sexual reproduction, the required protein machinery is poorly defined. In sperm cells, Izumo1 and several Izumo1-associated proteins play an essential role for this process. However, so far, the mechanisms underlying transport and maturation of Izumo1 and its incorporation into high molecular weight complexes are incompletely defined. Here, we provide a detailed characterization of the C11orf94 protein, which we rename Frey, which provides a platform for the assembly of Izumo1 complexes. By retaining Izumo1 in the endoplasmic reticulum, Frey facilitates its incorporation into high molecular weight complexes. To fulfill its function, the unstable Frey protein is stabilized within the catalytic center of an intramembrane protease. Loss of Frey results in reduced assembly of Izumo1 complexes and male infertility due to impaired gamete fusion. Collectively, these findings provide mechanistic insights into the early biogenesis and functional relevance of Izumo1 complexes.

1700029I15Rik orchestrates the biosynthesis of acrosomal membrane proteins required for sperm–egg interaction

“…Contreras et al. ( 42 ) discovered that 1700029I15Rik retains IZUMO1 in the ER of HeLa cells, contradicting with our observations that IZUMO1 colocalizes with 1700029I15Rik at the surface of COS-7 cells ( SI Appendix , Fig. S1 I ) and that coexpression with 1700029I15Rik does not prominently alter the subcellular expression pattern of IZUMO1 in HEK293T cells ( SI Appendix , Fig.…”

“…Recently, two independent studies on 1700029I15Rik were published ( 42 , 43 ). Despite that the knockout mouse lines exhibit the same phenotype, the works by three groups show great discrepancies in terms of the proposed molecular functions of 1700029I15Rik.…”

“…By immunohistochemistry, Contreras et al. observed that IZUMO1 shows reduced colocalization with BIP (also known as HSPA5) in the acrosomal granule of knockout spermatids as compared to the wild-type ( 42 ). We argue that additional evidence is required to support the conclusion that 1700029I15Rik mediates ER retention of IZUMO1 in vivo.…”

A novel function for the sperm adhesion protein IZUMO1 in cell–cell fusion

“…Proteins related to IZUMO1, for instance, IZUMO2-4, SPACA6, or TMEM95, may work as fusogens or potentiate IZUMO1’s fusogenic activity ( Deneke and Pauli, 2021 ). In this sense, IZUMO1 can form multiprotein complexes ( Contreras et al, 2022 ; Ellerman et al, 2009 ; Gaikwad et al, 2019 ). The absence of these proteins may explain the inability of somatic cells expressing IZUMO1 to fuse to eggs ( Fig.…”

Where are all the egg genes?

“…How are all the sperm and egg components assembled into complexes and at the right time and place? Genes are being discovered that may impact the processing and assembly of the fertilization synapse (Gleason et al, 2006;Contreras et al, 2022;Schreier et al, OPEN ACCESS EDITED BY Shao-Chen Sun, Nanjing Agricultural University, China 2022). For example, Frey can regulate the assembly of Izumo1, a key protein involved in fertilization on the surface of the sperm (Contreras et al, 2022).…”