Deciphering Glycosphingolipids as Drivers of a Novel Cell-Autonomous Immune Response

Pathogens exploit glycosphingolipids (GSLs) on the surface of gut epithelial cells to initiate infection. A recent breakthrough has uncovered a novel, cell-autonomous immune response in which multivalent clustering of GSLs by bacterial toxins or viruses triggers the degradation of the cell polarity protein PARD6B, leading to reduced pathogen uptake. This novel GSL-PARD6B pathway highlights the critical role of GSLs in mucosal immunity. However, the precise molecular mechanisms by which GSL binding initiates this intracellular signaling cascade and the subsequent changes to the host membrane composition are not fully understood. By integrating novel biochemical techniques with my existing skills in GSL-pathogen research, I will: 1)Define the triggering mechanism of the GSL-PARD6B pathway and, 2)Determine the effects of the microbiota and the GSL-PARD6B pathway on plasma membrane composition.This work will reveal how extracellular signals are translated across the plasma membrane to modulate intracellular responses and uncover mechanisms that protect against infection.Overall, the GlycoGuard project intends to provide a comprehensive understanding of the GSL-PARD6B pathway, advancing our knowledge of host-pathogen interactions and paving the way for novel therapeutic strategies against infections. Additionally, this grant will enhance my skills as a researcher and provide the foundation to establish myself as an independent scientist.