Viral DNA and leaked mitochondrial DNA (mtDNA) can trigger the cytosolic DNA sensor, cyclic GMP-AMP synthase (cGAS) to initiate the interferon (IFN) production signal cascade. Aberrant activation of the DNA sensing pathway can result in inflammatory and autoimmune diseases, such as systemic lupus erythematosus. However, how host limits excessive or detrimental immune responses to viral DNA and mtDNA is not well elucidated. Thus, it is pressing to define the protective mechanisms that prevent aberrant activation of cGAS- mediated innate immunity. Our overall objective in this application is to elucidate a host regulatory feedback mechanism that prevents cGAS from over-activating. Pilot experiments identified the complement C1q binding protein (C1QBP), a protein predominantly expressed in mitochondria as being associated with cGAS. Our pilot studies found that knockout of C1QBP augmented DNA-induced IFN response, suggesting C1QBP negatively regulates cGAS signaling. Our preliminary studies further discovered that viral infection-induced mitochondrial stress resulted in the release of C1QBP from mitochondria to the cytoplasm. Based on the existing literature and our preliminary data, we propose the following central hypothesis: Mitochondrial stress causes the release of C1QBP from mitochondria into cytosol. Direct interaction between cytosolic C1QBP and cGAS inhibits type I IFN expression, thereby providing a mechanism that prevents aberrant or sustained activation of innate immune responses.
Aim 1 will define the role of C1QBP in cytosolic DNA-mediated innate immunity in vitro and in vivo.
Aim 2 will determine the protective mechanisms by which C1QBP limits cytosolic DNA-induced cGAS activation. cGAS activity must be tightly regulated because sustained IFN production can lead to autoimmune diseases. This exploratory R21 application proposes C1QBP as a hidden host protector in mitochondria matrix. When mitochondria are damaged by infection and other cellular stresses, C1QBP is released from mitochondria to inhibit cGAS activity, thereby preventing excessive IFN response triggered by the leaked mtDNA. This study will elucidate an elegant host self-regulation mechanism, providing foundations for developing novel therapeutic strategies for infectious and autoimmune diseases.
Cytosolic DNA induces interferon, which plays a major role in host defense agaisnt DNA viruses and autoimmune diseases, such as systemic lupus erythematosus. This proposal aims to identify a new self- regulatory mechanism in DNA-mediated immunity. The discovery offers the potential to develop new therapeutics to prevent DNA virus infection and treatment of autoimmune diseases.
|Patil, Girish; Zhao, Mengmeng; Song, Kun et al. (2018) TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Influenza A Virus Infection. J Virol 92:|