The role of spatio-temporal nano-organization in regulating the specificity of JAK/STAT signaling

• Applicant: Professor Dr. Jacob Piehler
• Subject Area: Cell Biology
• Term: from 2015 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 284120884

Ligand-induced signal propagation through specific receptors in the plasma membrane is a key process for the cell in order to fulfill its complex role within multicellular organisms. While principal paradigms of how this process is mediated by different receptor types have been established, the molecular and biophysical parameters, which control the specificity of signal activation by the ligand, are far from being clear. A key challenge is to understand the so-called paradox of signaling specificity where a limited set of intracellular signaling effectors can control myriads of signaling outputs. The overall aim of this interdisciplinary and collaborative project is to uncover how the specificity of JAK/STAT signaling specificity is controlled by the nano-compartmentalization of the activated interferon-receptor (IFNR) complexes at the plasma membrane and in endosomes. IFNRs represent one of the best paradigms to investigate the complexity of these mechanisms since both type I IFNAR and type II IFNGR activate a common STAT1 molecule but display a distinct transcriptional output. The Lamaze group (P1) has recently shown that IFNR endocytic trafficking and lipid-based nano-organization at the plasma membrane play a key role in the selectivity of JAK/STAT activation by type I and type II interferons (IFNs), respectively. The Piehler group (P2) has established advanced imaging techniques for monitoring IFNR assembly and spatiotemporal dynamics using single molecule localization imaging techniques. The role of plasma membrane nano-compartmentalization into actin and lipid-based domains will be explored by using biochemical and genetic modifications. Specifically, we aim to identify how specific features of IFNGR localization into lipid rafts, are probably related to specific lipid and galectin interactions. We will identify new interaction partners by mass spectrometry (P1), which will be validated in living cells by functional surface micropatterning (P2). The role of these interaction partners in IFNR signaling will be further elucidated by biophysical (P2) and functional studies (P1). Based on the detailed mechanistic picture obtained from these studies, we will attempt to systematically swap functional modules between the type I and type II IFN receptors in order to validate their functional relevance in a specific cellular context (P1).

• DFG Programme: Research Grants
• International Connection: France
• Partner Organisation: Agence Nationale de la Recherche / The French National Research Agency
• Cooperation Partner: Dr. Christophe Lamaze