The Gokhale Lab is dedicated to understanding how RNA interacts with and regulates immune signaling complexes to control antiviral and inflammatory responses.

Our research combines immunology, RNA biology, and virology to uncover fundamental mechanisms and new therapeutic strategies.

Innate immune responses are activated when sentinel proteins in the RIG-I-like receptor (RLR), Toll-like receptor (TLRs), or NOD-like receptor families sense pathogenic ligands to initiate signaling cascades aimed at defending the host. A unifying feature of innate immune signaling is the formation of higher order multi-protein signaling complexes organized around central adaptors that coalesce at the right times and at the right subcellular locations. These signaling platforms need to be tightly regulated to control pathogens while limiting aberrant inflammation. Therefore, studying how these pathways are regulated has broad implications for understanding and therapeutically targeting both infection and autoimmunity.

RNA binding can alter interactions within and scaffold protein complexes or act as an allosteric ligand to modulate function. Around 25% of human proteins are proposed to bind RNA, often through uncharacterized or disordered domains, but the functional consequences of most protein-RNA interactions are completely unknown.

Viruses need to subvert innate immune responses and co-opt cellular RNA metabolism for their replication.

CURRENT RESEARCH AREAS

Viral RNA sensing by RIG-I-like receptors triggers the formation of a higher-order multi-protein signaling complex centered on the adaptor protein MAVS, ultimately inducing interferons and an antiviral state. We have identified that cellular mRNAs interact with the disordered domain of MAVS and promote its function by altering functional protein-protein interactions at the MAVS signalosome.

We are currently investigating (1) how the MAVS disordered region contributes to RNA-binding and MAVS function, (2) how RNA-modulated MAVS interacting proteins regulate antiviral immunity, and (3) the role of specific mRNAs in promoting MAVS function.

We are also studying (4) similar riboregulation of immune signaling complexes that form during Toll-like receptor and NOD-like receptor signaling.