Sexual reproduction is such a successful way of creating progeny with subtle genetic variations that the vast majority of eukaryotic species use it. In mammals, it involves the formation of highly ...specialised cells: the sperm in males and the egg in females, each carrying the genetic inheritance of an individual. The interaction of sperm and egg culminates with the fusion of their cell membranes, triggering the molecular events that result in the formation of a new genetically distinct organism. Although we have a good cellular description of fertilisation in mammals, many of the molecules involved remain unknown, and especially the identity and role of cell surface proteins that are responsible for sperm-egg recognition, binding, and fusion. Here, we will highlight and discuss these gaps in our knowledge and how the role of some recently discovered sperm cell surface and secreted proteins contribute to our understanding of this fundamental process.
Fertilization occurs when sperm and egg recognize each other and fuse to form a new, genetically distinct organism. The molecular basis of sperm-egg recognition is unknown, but is likely to require ...interactions between receptor proteins displayed on their surface. Izumo1 is an essential sperm cell-surface protein, but its receptor on the egg has not been described. Here we identify folate receptor 4 (Folr4) as the receptor for Izumo1 on the mouse egg, and propose to rename it Juno. We show that the Izumo1-Juno interaction is conserved within several mammalian species, including humans. Female mice lacking Juno are infertile and Juno-deficient eggs do not fuse with normal sperm. Rapid shedding of Juno from the oolemma after fertilization suggests a mechanism for the membrane block to polyspermy, ensuring eggs normally fuse with just a single sperm. Our discovery of an essential receptor pair at the nexus of conception provides opportunities for the rational development of new fertility treatments and contraceptives.
The spike protein of SARS-CoV-2 is known to enable viral invasion into human cells through direct binding to host receptors including ACE2. An alternate entry receptor for the virus was recently ...proposed to be basigin/CD147. These early studies have already prompted a clinical trial and multiple published hypotheses speculating on the role of this host receptor in viral infection and pathogenesis. Here, we report that we are unable to find evidence supporting the role of basigin as a putative spike binding receptor. Recombinant forms of the SARS-CoV-2 spike do not interact with basigin expressed on the surface of human cells, and by using specialized assays tailored to detect receptor interactions as weak or weaker than the proposed basigin-spike binding, we report no evidence for a direct interaction between the viral spike protein to either of the two common isoforms of basigin. Finally, removing basigin from the surface of human lung epithelial cells by CRISPR/Cas9 results in no change in their susceptibility to SARS-CoV-2 infection. Given the pressing need for clarity on which viral targets may lead to promising therapeutics, we present these findings to allow more informed decisions about the translational relevance of this putative mechanism in the race to understand and treat COVID-19.
The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and protect the fetus during ...pregnancy. Extravillous trophoblast cells (EVTs) derived from placental villi infiltrate the decidua, transforming the maternal arteries into high-conductance vessels
. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia
. Here we have generated a spatially resolved multiomics single-cell atlas of the entire human maternal-fetal interface including the myometrium, which enables us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to infer the possible transcription factors mediating EVT invasion and show that they are preserved in in vitro models of EVT differentiation from primary trophoblast organoids
and trophoblast stem cells
. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We predict the cell-cell communication events contributing to trophoblast invasion and placental bed giant cell formation, and model the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provide a comprehensive analysis of postimplantation trophoblast differentiation that can be used to inform the design of experimental models of the human placenta in early pregnancy.
During blood stage Plasmodium falciparum infection, merozoites invade uninfected erythrocytes via a complex, multistep process involving a series of distinct receptor-ligand binding events. ...Understanding each element in this process increases the potential to block the parasite's life cycle via drugs or vaccines. To investigate specific receptor-ligand interactions, they were systematically blocked using a combination of genetic deletion, enzymatic receptor cleavage and inhibition of binding via antibodies, peptides and small molecules, and the resulting temporal changes in invasion and morphological effects on erythrocytes were filmed using live cell imaging. Analysis of the videos have shown receptor-ligand interactions occur in the following sequence with the following cellular morphologies; 1) an early heparin-blockable interaction which weakly deforms the erythrocyte, 2) EBA and PfRh ligands which strongly deform the erythrocyte, a process dependant on the merozoite's actin-myosin motor, 3) a PfRh5-basigin binding step which results in a pore or opening between parasite and host through which it appears small molecules and possibly invasion components can flow and 4) an AMA1-RON2 interaction that mediates tight junction formation, which acts as an anchor point for internalization. In addition to enhancing general knowledge of apicomplexan biology, this work provides a rational basis to combine sequentially acting merozoite vaccine candidates in a single multi-receptor-blocking vaccine.
All the symptoms and pathology of malaria are caused by the intraerythrocytic stages of the Plasmodium parasite life cycle. Because Plasmodium parasites cannot replicate outside a host cell, their ...ability to recognize and invade erythrocytes is an essential step for both parasite survival and malaria pathogenesis. This makes invasion a conceptually attractive vaccine target, especially because it is one of the few stages when the parasite is directly exposed to the host humoral immune system. This apparent vulnerability, however, has been countered by the parasite, which has evolved sophisticated molecular mechanisms to evade the host immune response so that parasites asymptomatically replicate within immune individuals. These mechanisms include the expansion of parasite invasion ligands, resulting in multiple and apparently redundant invasion "pathways", highly polymorphic parasite surface proteins that are immunologically distinct, and parasite proteins which are poorly immunogenic. These formidable defences have so far thwarted attempts to develop an effective blood-stage vaccine, leading many to question whether there really is an exploitable chink in the parasite's immune evasion defences. Here, we review recent advances in the molecular understanding of the P. falciparum erythrocyte invasion field, discuss some of the challenges that have so far prevented the development of blood-stage vaccines, and conclude that the parasite invasion ligand RH5 represents an essential pinch point that might be vulnerable to vaccination.
Fertilization is the culminating event of sexual reproduction, which involves the union of the sperm and egg to form a single, genetically distinct organism. Despite the fundamental role of ...fertilization, the basic mechanisms involved have remained poorly understood. However, these mechanisms must involve an ordered schedule of cellular recognition events between the sperm and egg to ensure successful fusion. In this article, we review recent progress in our molecular understanding of mammalian fertilization, highlighting the areas in which genetic approaches have been particularly informative and focusing especially on the roles of secreted and cell surface proteins, expressed in a sex-specific manner, that mediate sperm-egg interactions. We discuss how the sperm interacts with the female reproductive tract, zona pellucida, and the oolemma. Finally, we review recent progress made in elucidating the mechanisms that reduce polyspermy and ensure that eggs normally fuse with only a single sperm.
The molecular mechanism of sperm-egg fusion is a long-standing mystery in reproduction. Brukman and colleagues (2022. J. Cell Biol.https://doi.org/10.1083/jcb.202207147) now provide evidence that the ...sperm surface protein IZUMO1, which is essential for mammalian fertilization, can induce membrane fusion in cultured cells.
Cellular fusion is required in the development of several tissues, including skeletal muscle. In vertebrates, this process is poorly understood and lacks an in vivo-validated cell surface ...heterophilic receptor pair that is necessary for fusion. Identification of essential cell surface interactions between fusing cells is an important step in elucidating the molecular mechanism of cellular fusion. We show here that the zebrafish orthologues of JAM-B and JAM-C receptors are essential for fusion of myocyte precursors to form syncytial muscle fibres. Both jamb and jamc are dynamically co-expressed in developing muscles and encode receptors that physically interact. Heritable mutations in either gene prevent myocyte fusion in vivo, resulting in an overabundance of mononuclear, but otherwise overtly normal, functional fast-twitch muscle fibres. Transplantation experiments show that the Jamb and Jamc receptors must interact between neighbouring cells (in trans) for fusion to occur. We also show that jamc is ectopically expressed in prdm1a mutant slow muscle precursors, which inappropriately fuse with other myocytes, suggesting that control of myocyte fusion through regulation of jamc expression has important implications for the growth and patterning of muscles. Our discovery of a receptor-ligand pair critical for fusion in vivo has important implications for understanding the molecular mechanisms responsible for myocyte fusion and its regulation in vertebrate myogenesis.
The malaria parasite Plasmodium falciparum replicates within erythrocytes, producing progeny merozoites that are released from infected cells via a poorly understood process called egress. The most ...abundant merozoite surface protein, MSP1, is synthesized as a large precursor that undergoes proteolytic maturation by the parasite protease SUB1 just prior to egress. The function of MSP1 and its processing are unknown. Here we show that SUB1-mediated processing of MSP1 is important for parasite viability. Processing modifies the secondary structure of MSP1 and activates its capacity to bind spectrin, a molecular scaffold protein that is the major component of the host erythrocyte cytoskeleton. Parasites expressing an inefficiently processed MSP1 mutant show delayed egress, and merozoites lacking surface-bound MSP1 display a severe egress defect. Our results indicate that interactions between SUB1-processed merozoite surface MSP1 and the spectrin network of the erythrocyte cytoskeleton facilitate host erythrocyte rupture to enable parasite egress.
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•Merozoite surface protein MSP1 processing is important for P. falciparum viability•Proteolytic processing activates MSP1’s heparin and spectrin-binding functions•The rate of MSP1 processing governs the kinetics of parasite egress•Loss of parasite surface MSP1 results in a severe egress defect
Egress from infected RBCs is a critical, but poorly understood, step in the malaria parasite’s lifecycle. Das et al. report that just prior to egress, proteolytic processing of parasite surface protein MSP1 activates a spectrin binding function, allowing the intracellular parasite to interact with the RBC cytoskeleton and enabling egress.
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