2. Academic Validation
  3. The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses

The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses

  • Cell Rep. 2025 Jan 28;44(1):115094. doi: 10.1016/j.celrep.2024.115094.
Chan Hoon Jung 1,  Yoon Jee Lee 1,  Eun Hye Cho 1,  Gee Eun Lee 1,  Sung Tae Kim 2,  Ki Sa Sung 3,  Daeho Kim 4,  Dong Hyun Kim 5,  Yeon Sung Son 6,  Jin-Hyun Ahn 7,  Dohyun Han 8,  Yong Tae Kwon 9
Affiliations

Affiliations

  • 1 Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea.
  • 2 Regeners, Inc., BVC 112, 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of Korea.
  • 3 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 4 Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.
  • 5 Cancer Metastasis Brach, Division of Cancer Biology, National Cancer Center, Goyang-si Gyeonggi-do 10408, Republic of Korea.
  • 6 Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea; Neuroscience Research Institute, Medical Research Center, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea.
  • 7 Department of Microbiology, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of Korea.
  • 8 Department of Transdisciplinary Medicine, Seoul National University Hospital, Seoul 03082, Republic of Korea; Department of Medicine, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea. Electronic address: hdh03@snu.ac.kr.
  • 9 Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea; Convergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul 110-799, Republic of Korea; AUTOTAC Bio, Inc., Changkkyunggung-ro 254, Jongno-gu, Seoul 03077, Republic of Korea; Ischemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea. Electronic address: yok5@snu.ac.kr.
PMID: 39709605 DOI: 10.1016/j.celrep.2024.115094
Abstract

The human body reacts to tissue damage by generating damage-associated molecular patterns (DAMPs) that activate sterile immune responses. To date, little is known about how DAMPs are removed to avoid excessive immune responses. Here, we show that proteasomal dysfunction induces the release of mitochondrial DNA (mtDNA) as a DAMP that activates the Cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon gene (STING) pathway and is subsequently degraded through the N-degron pathway. In the resolution phase of sterile immune responses, DNA-dependent protein kinase (DNA-PK) senses cytosolic mtDNA and activates N-terminal (Nt-) arginylation by ATE1 R-transferases. The substrates of Nt-arginylation include the molecular chaperone BiP/GRP78 retrotranslocated from the endoplasmic reticulum (ER). R-BiP, the Nt-arginylated species of BiP, is associated with cytosolic mtDNA to accelerate its targeting to autophagic membranes for lysosomal degradation. Thus, cytosolic mtDNA activates the N-degron pathway to facilitate its own degradation and form a negative feedback loop, by which the cell can turn off sterile immune responses at the right time.

Keywords

ATE1; CP: Immunology; DNA-PK; KU70; R-BiP; autophagy; mitochondrial DNA; proteasomal dysfunction; sterile immune response; the N-degron pathway; type I interferon.

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