The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses
Summary: 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...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724014451 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850244203941986304 |
|---|---|
| author | Chan Hoon Jung Yoon Jee Lee Eun Hye Cho Gee Eun Lee Sung Tae Kim Ki Sa Sung Daeho Kim Dong Hyun Kim Yeon Sung Son Jin-Hyun Ahn Dohyun Han Yong Tae Kwon |
| author_facet | Chan Hoon Jung Yoon Jee Lee Eun Hye Cho Gee Eun Lee Sung Tae Kim Ki Sa Sung Daeho Kim Dong Hyun Kim Yeon Sung Son Jin-Hyun Ahn Dohyun Han Yong Tae Kwon |
| author_sort | Chan Hoon Jung |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-352d7fb146d04df3b5e2fe3ec2d3130c |
| institution | OA Journals |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-352d7fb146d04df3b5e2fe3ec2d3130c2025-08-20T01:59:48ZengElsevierCell Reports2211-12472025-01-0144111509410.1016/j.celrep.2024.115094The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responsesChan Hoon Jung0Yoon Jee Lee1Eun Hye Cho2Gee Eun Lee3Sung Tae Kim4Ki Sa Sung5Daeho Kim6Dong Hyun Kim7Yeon Sung Son8Jin-Hyun Ahn9Dohyun Han10Yong Tae Kwon11Cellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of KoreaCellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of KoreaCellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of KoreaCellular Degradation Biology Center and Department of Biomedical Sciences, College of Medicine, Seoul National University, Seoul 03080, Republic of KoreaRegeners, Inc., BVC 112, 125 Gwahak-ro, Yuseong-gu, Daejeon, Republic of KoreaDepartment of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USADepartment of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USACancer Metastasis Brach, Division of Cancer Biology, National Cancer Center, Goyang-si Gyeonggi-do 10408, Republic of KoreaCellular 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 KoreaDepartment of Microbiology, Sungkyunkwan University School of Medicine, Suwon 16419, Republic of KoreaDepartment 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; Corresponding authorCellular 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; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124724014451CP: Immunology |
| spellingShingle | Chan Hoon Jung Yoon Jee Lee Eun Hye Cho Gee Eun Lee Sung Tae Kim Ki Sa Sung Daeho Kim Dong Hyun Kim Yeon Sung Son Jin-Hyun Ahn Dohyun Han Yong Tae Kwon The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses Cell Reports CP: Immunology |
| title | The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses |
| title_full | The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses |
| title_fullStr | The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses |
| title_full_unstemmed | The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses |
| title_short | The N-degron pathway mediates the autophagic degradation of cytosolic mitochondrial DNA during sterile innate immune responses |
| title_sort | n degron pathway mediates the autophagic degradation of cytosolic mitochondrial dna during sterile innate immune responses |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724014451 |
| work_keys_str_mv | AT chanhoonjung thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT yoonjeelee thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT eunhyecho thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT geeeunlee thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT sungtaekim thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT kisasung thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT daehokim thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT donghyunkim thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT yeonsungson thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT jinhyunahn thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT dohyunhan thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT yongtaekwon thendegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT chanhoonjung ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT yoonjeelee ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT eunhyecho ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT geeeunlee ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT sungtaekim ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT kisasung ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT daehokim ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT donghyunkim ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT yeonsungson ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT jinhyunahn ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT dohyunhan ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses AT yongtaekwon ndegronpathwaymediatestheautophagicdegradationofcytosolicmitochondrialdnaduringsterileinnateimmuneresponses |