Date of Completion

11-30-2018

Embargo Period

5-1-2019

Keywords

Interferon, Gasdermin, DNA sensing, Innate Immunity, Inflammasome

Major Advisor

Vijay Rathinam, DVM, PhD

Associate Advisor

Anthony Vella, PhD

Associate Advisor

Kamal Khanna, PhD

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

DNA released into the cytoplasm as a consequence of microbial infection or pathology can be recognized by the host sensor, Absent in melanoma (AIM) 2 that leads to the assembly and activation of the inflammasome complex and cyclic GMP-AMP synthase (cGAS) that induces type-I Interferon (IFN) production. Inflammasome activated caspase-1 cleaves gasdermin-D leading to pore-formation in the plasma membrane that subsequently results in pyroptosis. In this study we found that activated gasdermin-D negatively regulates cGAS-induced type-I IFN production in a pyroptosis and interleukin (IL)-1b and IL-18 independent manner. Mechanistic studies showed that gasdermin-D pore formation lead to a loss of intracellular potassium (K+) concentration that suppressed the production of cGAS-induced type-I IFN. Therefore, we report a novel regulatory mechanism for cGAS/STING-induced type-I IFN that may have profound therapeutic implications in autoimmune diseases and anti-tumor immunotherapy.

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