Erin Doherty, Ph.D., Berkeley Chancellor's Postdoctoral Fellow / NIH F32 NRSA Fellow, UC Berkeley

Speaker:

Erin Doherty, Ph.D.

Berkeley Chancellor's Postdoctoral Fellow / NIH F32 NRSA Fellow

UC Berkeley

Faculty Host: Michelle O'Malley

Title: Chemical Diversification of Signaling Expands Immune Defense Strategies

Abstract: 

Nucleotides have evolved beyond carriers of genetic information to become versatile molecules central to immune signaling. Cyclic oligonucleotides are key components of microbial and human immunity, and the pathways that use them share striking mechanistic similarities. In these pathways, including CBASS and type III CRISPR systems in bacteria and cGAS-STING in humans, cyclic oligonucleotide synthesis is triggered by virus or foreign genetic material, and these signals activate the cell's anti-viral response. We used chemical and structural biology to identify a surprising inversion of this paradigm: the CRISPR-related enzyme mCpol synthesizes a chemically distinct cyclic oligonucleotide (2'3'-c-di-AMP) to suppress, as opposed to activate, the anti-viral response. Therefore, loss of mCpol-produced 2'3'-c-di-AMP prevents the spread of viruses that attempt immune evasion by depleting host cyclic oligonucleotides. These findings unveil a powerful defense strategy against virus-mediated immune suppression, expanding our understanding of oligonucleotides in cell health and disease. This work illustrates how nucleotide chemistry enables divergent modes of immunity, provides a major constraint for viral evolution, and suggests the possibility of similar protective roles for cyclic oligonucleotides in other organisms including humans.

Bio:

Dr. Erin Doherty is a Berkeley Chancellor's Postdoctoral Fellow and NIH F32 NRSA Fellow in the laboratory of Jennifer Doudna at the University of California, Berkeley. Her postdoctoral work integrates chemical and structural biology to uncover fundamental mechanisms of immune signaling, with a particular focus on nucleotide-based signaling mechanisms conserved between prokaryotes and eukaryotes. Erin received her B.S. in Biochemistry from Cal Poly San Luis Obispo, conducting research in synthetic organic chemistry with H.H. Palandoken. She received her Ph.D. in the laboratory of Peter Beal at UC Davis, where her dissertation applied chemical biology to engineer therapeutic RNA editing systems.