By Merin C. MacDonald  | Date published: August 20, 2024

Egil Lien and Kate Fitzgerald Awarded Funding to Investigate Role of Splicing Factors in Inflammation and Cytotoxicity 

The splicing factors Raver1 and Ptbp1 regulate how pieces of RNA for RIPK1, a key inflammatory kinase, are spliced and assembled to make mRNA which is eventually translated into a full-length protein. RIPK1 is responsible for controlling several signaling pathways for inflammation and cell death, including signals involving an enzyme called caspase-8, and a pore-forming molecule called Gasdermin D. A lack of Raver1 and Ptpb1 leads to differences in RIPK1 expression and splicing, and to the production of a dysfunctional RIPK1 protein.  

In their newly funded project, Egil Lien, PhD, professor of medicine in the Division of Infectious Diseases and Immunology and faculty in the Program in Innate Immunity, and Kate Fitzgerald, PhD, the Worcester Foundation for Biomedical Research Chair III, professor of medicine, associate vice provost for basic science research, vice chair of research in the Department of Medicine, chief of the Division of Innate Immunity and director of the Program in Innate Immunity, will investigate how Raver1 and Ptbp1 contribute to the regulation of innate immunity, inflammation, cell death and host resistance to pathogens. The study team has proposed that RIPK1-caspase-8-Gasdermin D is central in host responses to infection with Yersinia bacteria, thus, the contributions of Raver1 and Ptbp1 are critical for directing a host defense mechanism. The project aims to determine the roles of Raver1 and Ptbp1 in inflammation and cytotoxicity, in vitro and in vivo.

In addition to Drs. Lien and Fitzgerald, key contributors to the project include Athma Pai, PhD, of the RNA Therapeutics Institute, and Michelle Kelliher, PhD, of Molecular, Cell and Cancer Biology.