Biology subjects

Lyndin, M.

Publications and source records attributed to Lyndin, M..

3 recordsLinked to original sources

bioRxiv2026

Soluble ZP2 N-terminal fragments activate CatSper-dependent Ca2+ entry and regulate motility and acrosomal exocytosis in mammalian sperm

Sperm motility and function are central to mammalian fertilization and are tightly regulated by intracellular calcium (CaCa2+) signaling. This signaling is primarily orchestrated by the CatSper Ca2+; channel complex located in the flagella of spermatozoa. However, the natural ligands that activate CatSper remain largely unknown in many species, despite the conservation of CatSper in mammals. Here, we present a signaling role for soluble N-terminal ZP2 fragments in regulating CatSper activity and sperm physiology in mice and humans. ZP2 has been implicated in mediating sperm binding and recognition at the oocyte surface interface; however, new evidence is starting to unveil the molecular mechanisms and function of ZP2 during fertilization transition. Here, we show that the during fertilization, cleaved ZP2 N-terminal fragment triggers a rapid and robust increase in intracellular CaCa2+ levels in sperm. This increase depends strictly on CatSper function, as demonstrated through pharmacological analysis and CatSper1 knockout mice. This calcium influx is sufficient to induce acrosomal exocytosis in a subset of human and mouse sperm. AlphaFold-based structural modeling suggests a potentially conserved extracellular interaction site between the soluble N-terminal ZP2 fragments and the CatSper complex. In human sperm, ZP2 treatment significantly modulates motility parameters, including flagellar movement and velocity, while inducing a CatSper-dependent increase in intracellular CaCa2+ similar in magnitude to that evoked by progesterone. Species-matched ZP2 stimulation elicits the stronger calcium response, underscoring evolutionary adaptations in ligand-channel protein pairs. Taken together, our findings reveal a conserved signaling pathway from ZP2 to CatSper that integrates oocyte-derived signals into the regulation of sperm motility and acrosomal exocytosis. This pathway provides new mechanistic insights into fertilization and highlights potential targets.

cell biology↗

bioRxiv2025

LILRA5 functions to induce ROS production on innate immune cells

Activating immune receptors provide mechanisms for phagocytes to elicit important effector functions that promote the killing of microbes. Leukocyte immunoglobulin-like receptor A5 (LILRA5) an orphan immune receptor expressed by human phagocytes and co-localising with FcR{gamma}, remains poorly characterised. To address this, we developed a highly-specific anti-LILRA5 monoclonal antibody that has agonistic properties. Using a specific anti-LILRA5 antibody, we show LILRA5 expression on naive monocytes and neutrophils, and that ligation of LILRA5 stimulates ROS production. While increased LILRA5 transcript copy numbers have been associated with sepsis, we also observed increased levels in patients with systemic infection but without sepsis complications. Ex vivo bacterial infection of whole blood did not alter surface LILRA5 expression, but LPS stimulation changed expression levels. This indicates that surface LILRA5 expression is dynamic and likely regulated posttranscriptionally, changing responses to different stimuli or over time. Soluble (s)LILRA5 was enhanced in sera from sepsis patients and in supernatants of monocytes that were LPS-stimulated, indicative that shedding of LILRA5 from cell surfaces or that expression of sLILRA5 isoforms provides a mechanism to regulate surface LILRA5 expression levels. Finally, we show that altered surface LILRA5 expression influences LILRA5-induced ROS production capacity. We propose that LILRA5 is a dynamically regulated activating receptor expressed on phagocytes that can stimulate ROS production.

immunology↗

bioRxiv2020

Bacterial protein domains with a novel Ig-like fold bind human CEACAM receptors

Streptococcus agalactiae, also known as group B Streptococcus (GBS), is the major cause of neonatal sepsis in humans. A critical step to infection is adhesion of bacteria at mucosal surfaces. Though several GBS adhesins have been identified, the host receptor targets of these adhesins remain unknown. We report here that surface-expressed {beta} protein from GBS binds to human CEACAM1 and CEACAM5 receptors. A crystal structure of the complex showed that the IgSF domain in {beta} represents a novel Ig-fold subtype called IgI3, in which unique features allow binding to CEACAM1. Bioinformatic assessments revealed that this newly identified IgI3 fold is not exclusively present in GBS. Instead, the IgI3 fold is predicted to be present in adhesins from other clinically important human pathogens. We confirmed the interaction between CEACAM1 and the predicted IgI3-containing adhesin in two different streptococcal pathogens. Overall, our results indicate that the IgI3 fold could provide a broadly applied mechanism for bacteria to target CEACAMs.

microbiology↗