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) the biochemical basis and consequences of the MAVS-RNA interaction, (2) the role of specific mRNAs in promoting MAVS function, and (3) how RNA-modulated MAVS interacting proteins regulate antiviral immunity.

Our work on cellular RNA control of the MAVS signalosome leads suggests that other innate immune signaling complexes may also be modulated by RNA-protein interactions. Is RNA-mediated control a shared feature across innate immune signaling? Therefore, we seek to uncover (4) similar riboregulatory processes in immune signaling complexes that form during Toll-like receptor, C-type lectin-like receptor signaling, and NOD-like receptor signaling. (5) We also aim to catalog how the RNA-binding proteome is remodeled by innate immune stimulus to identify and dissect the function of cryptic RNA-binding proteins in innate immunity and infection.