Page 282 - ebook

[E. Immunology] E-11

DNA-PKcs regulates immune signaling triggered by

mitochondrial DNA double-stranded Breaks

June Heo¹,², Ho-Soo Lee¹, Hyeseong Cho¹,²*

¹Biochemistry and Molecular Biology, Ajou University School of Medicine, Suwon 16499, Korea, ²Biomedical

Sciences, Graduate School of Ajou University, Suwon 16499, Korea

Mitochondrial DNA (mtDNA) encodes necessary genes for the generation of ATPs (adenosine triphosphates), which

are used as an energy source for intracellular activities. mtDNA is prone to double-stranded breaks damage caused
by replication errors, ultraviolet light, radiation, and various chemicals. Cleaved mtDNA is rapidly degraded by

mitochondrial replication machinery. During the processing of mitochondrial DNA double-strand breaks (mtDSBs),
some of mitochondrial nucleic acids are released into the cytoplasm and then trigger an aberrant innate immune

response. Persistency of immune signaling leads to host immunopathology. Here, using mitochondrial DNA-targeted
FokI endonucleases, we showed that mtDSBs triggered mtDNA degradation and activated type-I interferon response

and interferon-stimulated genes (ISGs) through DNA-PKcs-HSPA8 signaling axis. We also explored protein H
regulating mtDSBs-induced immune signaling and showed that reduced expression of mRNA of interferon β1 and

ISGs in response to overexpressing protein H. Our data suggest that protein H acts as a key molecule regulating
mtDSBs-induced immune signaling dependent on the DNA-PKcs-HSPA8 axis.