Epitranscriptomic Regulation of Type I Interferon


Ian J. Mohr, PhD
Professor, Department of Microbiology

Nearly 50 million Americans suffer from untreatable autoimmune diseases like Lupus, Crohn’s, Multiple Sclerosis. There is a spectrum of human lupus ranging from solely skin involvement to systemic disease, the common denominator being tissue damage resulting from the deposits of immune complexes that fix complement. Systemic disease is characterized by a relapsing and remitting course with flares of high morbidity. It has been long known that Type I Interferon pathway plays a key role in the disease progression however, there are no cure for the disease yet.

NYU inventor Ian Mohr and his team has now discovered that type I interferon (IFN) production triggered by double- strand (ds) DNA or human cytomegalovirus (HCMV) is controlled by the cellular m6A- methyltransferase subunit METTL14 and ALKBH5 demethylase. They have shown that depleting METTL14 reduced virus reproduction and stimulated dsDNA or HCMV-induced IFNβ mRNA accumulation. ALKBH5-depletion however, had the opposite effect. Genome-wide transcriptome profiling following ALKBH5-depletion have led to the identification of differentially-expressed genes regulating anti-viral immune responses, while METTL14-depletion altered pathways impacting metabolic reprogramming, stress responses, and aging.

The invention establishes that the host m6A modification machinery controls IFNβ production triggered by HCMV or dsDNA. Moreover, it demonstrates that responses to dsDNA in uninfected cells, which shape host immunity and contribute to autoimmune disease associated with non-microbial, cytoplasmic dsDNA signaling, are regulated by enzymes controlling m6A- epitranscriptomic changes.

Epitranscriptomics opens up a rich new target space, that is associated with autoimmunity. The invention would now allow an alternative signaling pathway to treat patients suffering from autoimmunity disorders by precisely targeting specific RNA modifying proteins.



Ananda Ghosh Ph.D.