Identification of a Novel Endogenous Small Molecule Suppressor of Innate Immunity

ASPIRE AWARD (2021-2023)

Matthew Meyerson, MD, PhD, Broad Institute and Dana-Farber Cancer Institute

Matthew Meyerson, MD, PhD

The cGAS/STING signaling axis senses the mislocalization of DNA to the cytosol and is an important component of the innate immune response for sensing infected, damaged, or abnormal cells. Notably, this pathway been implicated as critical for the metastatic potential of tumors with chromosomal instability and may represent a targetable node for new therapies. In a large study of genetic alterations in lung cancers, Matthew Meyerson of the Broad Institute of MIT and Harvard and the Dana-Farber Cancer Institute identified MB21D2, a novel enzyme that regulates this pathway. MB21D2 is closely related to cGAS, and both molecules are members of the nucleotidyltransferase family. It is well known that upon DNA sensing in the cytosol, cGAS catalyzes the formation of the dinucleotide cGAMP which stimulates STING signaling. In contrast, MB21D2 appears to catalyze the formation of a different dinucleotide which inhibits STING instead of activating it.

Meyerson, Wheeler, and colleagues are validating the composition and in vivo presence of the MB21D2 product and determining its role in innate immunity and cancer biology. Through enzymology and analytical chemistry, the team are working to verify the structure of the candidate product and determine which endogenous molecules can act as substrates of MB21D2. They are also characterizing the interaction between the product and STING and testing for the presence of the product in cells to confirm whether it can suppress signaling in cells. If they verify that the MB21D2 product is an endogenous small molecule that inhibits STING signaling, MB21D2 would represent a novel target for drug development in both oncology and immunology.