Date of Completion
Interferon, Gasdermin, DNA sensing, Innate Immunity, Inflammasome
Vijay Rathinam, DVM, PhD
Anthony Vella, PhD
Kamal Khanna, PhD
Field of Study
Doctor of Philosophy
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.
Banerjee, Ishita, "Cross-talk Between Different DNA Sensors in the Cytosol" (2018). Doctoral Dissertations. 2010.