Gideon Schreiber Lab

Protein-Protein Interaction

Research

My laboratory is engaged in understanding the intricate web of protein-protein interactions that underpin every aspect of living organisms. With a sharp focus on the structural and functional nuances of these interactions, our research unravels the molecular dialogue that governs biological signaling. We employ a multifaceted, interdisciplinary strategy that seamlessly integrates protein engineering and bioinformatics. These tools act as pivotal inputs to address complex biological queries. Among our key research themes is a comprehensive elucidation of the interferon signaling pathway—a crucial component of immune response. Moreover, we engaged in tracking the evolutionary journey of the SARS-CoV-2 virus, providing vital insights into pandemic progression and viral behavior. Our most recent endeavor involves the pioneering design of specialized exosomes. These are engineered with precision to transport RNA molecules, opening new vistas in the realm of therapeutic delivery systems. Each discovery propels us closer to decoding the language of life's molecular machinery, which brings us closer to treat diseases in a specific manner.

Research page

Cytokine signaling as a cascade of protein interactions for multiple outputs

Structure/function & evolution of protein interactions towards drug design

Targeted delivery of RNA using engineered exosomes

Investigate the role of interferons in CLL and Melanoma in mouse models

Selected Publications

Promiscuous Janus kinase binding to cytokine receptors modulates signaling efficiencies and contributes to cytokine pleiotropy

Zoler E., Meyer T., Bellón J. S., Mönnig M., Sun B., Piehler J. & Schreiber G. (2024) Science Signaling. 17, 863, eadl1892.

Janus kinases (JAKs) bind to class I and II cytokine receptors, activating signaling and regulating gene transcription through signal transducer and activator of transcription (STAT) proteins. Type I interferons (IFNs) require the JAK members TYK2 and JAK1, which bind to the receptor subunits IFNAR1 and IFNAR2, respectively. We investigated the role of JAKs in regulating IFNAR signaling activity. Synthetic IFNARs in which the extracellular domains of IFNAR1 and IFNAR2 are replaced with nanobodies had near-native type I IFN signaling, whereas the homomeric variant of IFNAR2 initiated much weaker signaling, despite harboring docking sites for JAKs and STATs. Cells with JAK1 and TYK2 knockout (KO) showed residual signaling, suggesting partial complementation by the remaining JAKs, particularly when they were overexpressed. Live-cell micropatterning experiments confirmed the promiscuous binding of JAK1, JAK2, and TYK2 to IFNAR1 and IFNAR2, and their recruitment correlated with their relative cellular abundances. However, each JAK had a different efficacy in inducing cross-phosphorylation and downstream signaling. JAK binding was also promiscuous for other cytokine receptors, including IFN-L1, IL-10Rβ, TPOR, and GHR, but not for EPOR, which activated different downstream signaling pathways. These findings suggest that competitive binding of JAKs to cytokine receptors together with the varying absolute and relative abundances of the JAKs in different cell types can account for the cell typedependent signaling pleiotropy of cytokine receptors.

Variant-proof high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways

Gagne M., Flynn B. J., Honeycutt C. C., Flebbe D. R., Andrew S. F., Provost S. J., McCormick L., Van Ry A., McCarthy E., Todd J. P. M., Bao S., Teng I. T., Marciano S., Rudich Y., Li C., Jain S., Wali B., Pessaint L., Dodson A., Cook A., Lewis M. G., Andersen H., Zahradník J., Suthar M. S., Nason M. C., Foulds K. E., Kwong P. D., Roederer M., Schreiber G., Seder R. A. & Douek D. C. (2024) Nature Communications. 15, 6894.

SARS-CoV-2 has the capacity to evolve mutations that escape vaccine- and infection-acquired immunity and antiviral drugs. A variant-agnostic therapeutic agent that protects against severe disease without putting selective pressure on the virus would thus be a valuable biomedical tool that would maintain its efficacy despite the ongoing emergence of new variants. Here, we challenge male rhesus macaques with SARS-CoV-2 Deltathe most pathogenic variant in a highly susceptible animal model. At the time of challenge, we also treat the macaques with aerosolized RBD-62, a protein developed through multiple rounds of in vitro evolution of SARS-CoV-2 RBD to acquire 1000-fold enhanced ACE2 binding affinity. RBD-62 treatment equivalently suppresses virus replication in both upper and lower airways, a phenomenon not previously observed with clinically approved vaccines. Importantly, RBD-62 does not block the development of virus-specific T- and B-cell responses and does not elicit anti-drug immunity. These data provide proof-of-concept that RBD-62 can prevent severe disease from a highly virulent variant.

Harnessing the power of IFN for therapeutic approaches to COVID-19

G. V. E., E. B. S., C. D. D., Gideon S. & Mirko P. (2024) Journal of Virology. 98, 5, e01204-23.

Interferons (IFNs) are essential for defense against viral infections but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. Here, we explore the complexity of the IFN response in COVID-19, examine the effects of manipulating IFN on SARS-CoV-2 viral replication and pathogenesis, and highlight pre-clinical and clinical studies evaluating the therapeutic efficacy of IFN in limiting COVID-19 severity.

All Publications