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

Brukman, Nicolás G.; Nakajima, Kohdai P.; Valansi, Clari; Flyak, Kateryna; Li, Xiaohui; Higashiyama, Tetsuya; Podbilewicz, Benjamin

doi:10.1083/jcb.202207147

Cited by 21 publications

(30 citation statements)

References 99 publications

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“…A recent article reported that the tryptophan at position 148 of IZUMO1 was crucial for the binding with JUNO (Brukman et al., 2023). This position is not affected by positive selection and is completely conserved in all Carnivora species.…”

Section: Discussionmentioning

confidence: 99%

“…The interaction between JUNO and IZUMO1 is essential for sperm to dock to the surface of an egg (Bianchi et al., 2014), a crucial recognition step prior to membrane fusion (Inoue et al., 2015). Although neither protein has been conclusively shown to be a fusogen, there is recent evidence that IZUMO1 may have fusogenic activity (Brukman et al., 2023).…”

Section: Introductionmentioning

confidence: 99%

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Positive selection in gamete interaction proteins in Carnivora

Pisciottano,

Campos,

Penna

et al. 2024

Molecular Ecology

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The absence of robust interspecific isolation barriers among pantherines, including the iconic South American jaguar (Panthera onca), led us to study molecular evolution of typically rapidly evolving reproductive proteins within this subfamily and related groups. In this study, we delved into the evolutionary forces acting on the zona pellucida (ZP) gamete interaction protein family and the sperm‐oocyte fusion protein pair IZUMO1‐JUNO across the Carnivora order, distinguishing between Caniformia and Feliformia suborders and anticipating few significant diversifying changes in the Pantherinae subfamily. A chromosome‐resolved jaguar genome assembly facilitated coding sequences, enabling the reconstruction of protein evolutionary histories. Examining sequence variability across more than 30 Carnivora species revealed that Feliformia exhibited significantly lower diversity compared to its sister taxa, Caniformia. Molecular evolution analyses of ZP2 and ZP3, subunits directly involved in sperm‐recognition, unveiled diversifying positive selection in Feliformia, Caniformia and Pantherinae, although no significant changes were linked to sperm binding. Structural cross‐linking ZP subunits, ZP4 and ZP1 exhibited lower levels or complete absence of positive selection. Notably, the fusion protein IZUMO1 displayed prominent positive selection signatures and sites in basal lineages of both Caniformia and Feliformia, extending along the Caniformia subtree but absent in Pantherinae. Conversely, JUNO did not exhibit any positive selection signatures across tested lineages and clades. Eight Caniformia‐specific positive selected sites in IZUMO1 were detected within two JUNO‐interaction clusters. Our findings provide for the first time insights into the evolutionary trajectories of ZP proteins and the IZUMO1‐JUNO gamete interaction pair within the Carnivora order.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Positive selection in gamete interaction proteins in Carnivora

Pisciottano,

Campos,

Penna

et al. 2024

Molecular Ecology

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“…Mammalian sperm‐egg adhesion is believed to depend on the transinteraction between the sperm‐specific IZUMO1 and oocyte‐specific GPI‐anchored receptor JUNO 31 . A reduction in fusion occurs when sperm are treated with antibodies against IZUMO1, 30 and artificially expressed IZUMO1 induces cell‐to‐cell fusion in cultured somatic cells 32 . These findings indicate that IZUMO1 acts as a fusogen that is physiologically restrictively expressed in sperm cells during fertilization.…”

Section: Discussionmentioning

confidence: 99%

Implication of IZUMO2 in the cell‐in‐cell phenomenon: A potential therapeutic target for triple‐negative breast cancer

Higashi,

Saigo,

Chikaishi

et al. 2024

Thoracic Cancer

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BackgroundTriple‐negative breast cancer (TNBC) is characterized by the loss of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. The aggressive clinicopathological features and resistance to currently available therapeutics of the disease warrant an urgent need for the development of novel alternate therapeutic options. We have previously reported adiponectin‐expressing regulatory T cells (A‐Tregs), which can induce apoptosis in TNBC through the cell‐in‐cell phenomenon. In this study, we aimed to elucidate the molecule that allows TNBC cells to engulf A‐Tregs.MethodsA monoclonal antibody, which repressed the engulfment of A‐Tregs by TNBC cells, was developed. Immunoprecipitation followed by mass spectrometry and small interfering RNAs‐mediated gene silencing was performed to characterize the antigen.ResultsWe successfully generated a monoclonal antibody, designated G1D7, which abrogated the engulfment of A‐Tregs by TNBC and subsequent A‐Treg‐mediated apoptosis. G1D7 detected the immunoglobulin‐like type I membrane protein IZUMO2, a molecule related to IZUMO1 that is essential for cell–cell membrane binding and fusion of sperm to oocyte.ConclusionThe findings highlight the importance of IZUMO2 on TNBC cells in facilitating the cell‐in‐cell phenomenon by A‐Tregs.

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“…A recent article reported that the tryptophan at position 148 of IZUMO1 was crucial for the binding with JUNO (Brukman et al, 2023). This position is not affected by positive selection and is completely conserved in all Carnivora species.…”

Section: Discussionmentioning

confidence: 99%

Positive selection in gamete interaction proteins inCarnivora

Pisciottano

Campos

Penna

et al. 2022

Preprint

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The jaguar (Panthera onca) is the most relevant predator in South America and an endangered species in Argentina. Therefore genomic, evolutionary and functional studies of this species are strategic to gain biological insights and support conservation efforts. With the advent of sequencing advances the study of relevant character species evolution has to be revisited. Recent comparative genomic analysis revealed a long history of hybridization among extant big cats, which indicates an absence of inter-specific isolation barriers. We aimed to uncover the molecular basis of this interspecies crossing and the evolution of the functional capacities of pantherine gamete interaction Zona Pellucida proteins (ZP) and JUNO. Hi-C long-range sequencing and chromosome-resolved jaguar genome assembly was used to resolve ZP genes loci and reconstruct the evolutionary history of these proteins. Exploring sequence variability in more that 30 Carnivora species, Feliforme and Caniforme sister groups show significant differences in average sequence identity for all studied proteins except ZP4, always showing Caniformes as a more diverse group than Feliformes. Molecular evolution of ZP isoforms involved in sperm-recognition, ZP3 and ZP2, showed similar phylogenetic histories, displaying signatures of positive selection among Carnivores and Caniformes, but not among Pantherines or Feliformes. On the other hand, structural cross-linking ZP subunits, ZP1 and ZP4, displayed a different evolutionary history. The fusion protein IZUMO1R was found to be highly conserved in all studied phylogenetic groups. These results strengthen the idea that ZPs are proteins more related to specific-specificity isolation than IZUMO1R, which is specialized in fusion events. Altogether, our findings indicate that sperm-oocyte interaction and fusion proteins lack the degree of diversification necessary to establish a prezygotic reproductive isolation barrier between pantherines, which would explain observed reticulated patterns of evolution in this clade.

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

Cited by 21 publications

References 99 publications

Positive selection in gamete interaction proteins in Carnivora

Positive selection in gamete interaction proteins in Carnivora

Implication of IZUMO2 in the cell‐in‐cell phenomenon: A potential therapeutic target for triple‐negative breast cancer

Positive selection in gamete interaction proteins inCarnivora

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