Role of TXLNA in cytosolic DNA-mediated innate immunity

Project summary Exposure to cytosolic DNA from infectious pathogens triggers the expression of type I interferon (IFN) through the cGAS-STING signaling pathway. However, cGAS cannot discern the source and sequence of DNA, making it susceptible to activation by cytosolic DNA leaked from damaged nuclei or mitochondria. Dysregulated activation of the cGAS-STING pathway has been linked to autoimmune diseases, including systemic lupus erythematosus (SLE). Currently, there is a significant knowledge gap in our understanding of how and why TBK1 is recruited to the STING complex at the Golgi. The activation and inhibition of STING have emerged as crucial therapeutic targets for both cancers and autoinflammatory conditions. Thus, there is a pressing need to elucidate the mechanisms by which STING recruits TBK1 at the Golgi to activate type I IFN. Our preliminary investigations have unveiled that taxilin alpha (TXLNA) is indispensable for IFN production in response to cytosolic DNA. Moreover, TXLNA interacts with both STING and TBK1. Prior research has indicated that TXLNA transgenic mice develop an SLE-like autoimmune disease attributed to excessive production of type I IFN, suggesting a link to innate immunity. Nevertheless, the role of TXLNA in innate immunity remains elusive. This project's overarching objective is to determine the role of TXLNA in STING- mediated TBK1 activation by employing a knockout mouse model and to pinpoint the regulatory mechanisms. Drawing from the existing literature and our preliminary data, we hypothesize that TXLNA regulates STING- mediated TBK1 activation. This proposal will investigate three aims: i) Determine the role of TXLNA in innate immunity and viral infection. ii) Test the hypothesis that TXLNA regulates TBK1 activation at the Golgi. iii) Dissect the mechanisms regulating TXLNA activity. The potential consequences of dysregulated IFN responses include heightened susceptibility to viral infections or adverse effects on the host due to an excessively active immune system. The mechanistic insights derived from this proposal will laying the groundwork for the development of innovative therapeutic strategies to combat infectious diseases and autoimmune disorders.