title: The kinase Jnk2 promotes stress-induced mitophagy by targeting the small mitochondrial form of the tumor suppressor ARF for degradation.
abstract: Mitophagy is essential for cellular homeostasis, but how mitophagy is regulated is largely unknown. Here we found that the kinase Jnk2 was required for stress-induced mitophagy. Jnk2 promoted ubiquitination and proteasomal degradation of the small mitochondrial form of the tumor suppressor ARF (smARF). Loss of Jnk2 led to the accumulation of smARF, which induced excessive autophagy that resulted in lysosomal degradation of the mitophagy adaptor p62 at steady state. Depletion of p62 prevented Jnk2-deficient cells from mounting mitophagy upon stress. Jnk2-deficient mice displayed defective mitophagy, which resulted in tissue damage under hypoxic stress, as well as hyperactivation of inflammasomes and increased mortality in sepsis. Our findings define a unique mechanism of maintaining immunological homeostasis that protects the host from tissue damage and mortality.
authors: 1] Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. [2] State Xinyuan Institute of Medicine and Biotechnology, College of Life Science, Zhejiang Sci-Tech University, Hangzhou, China.
authors: Qiao
authors: Q
authors: Zhang
authors: 1] Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. [2] State Xinyuan Institute of Medicine and Biotechnology, College of Life Science, Zhejiang Sci-Tech University, Hangzhou, China.
authors: Hong
authors: H
authors: Kuang
authors: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors: Cong
authors: C
authors: Chen
authors: Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois, USA.
authors: Jie
authors: J
authors: Yan
authors: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors: Hanh Chi
authors: HC
authors: Do-Umehara
authors: State Xinyuan Institute of Medicine and Biotechnology, College of Life Science, Zhejiang Sci-Tech University, Hangzhou, China.
authors: Xin-yuan
authors: XY
authors: Liu
authors: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors: Laura
authors: L
authors: Dada
authors: 1] Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. [2] Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois, USA.
authors: Karen M
authors: KM
authors: Ridge
authors: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors: Navdeep S
authors: NS
authors: Chandel
authors: Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
authors: Jing
authors: J
authors: Liu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D005260:Female; D000860:Hypoxia / Q000276:immunology*; D058847:Inflammasomes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism*; D063306:Mitophagy / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology*; D054875:Ubiquitination
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D058847:Inflammasomes; D008070:Lipopolysaccharides; D016271:Proto-Oncogene Proteins c-myc; D048056:Mitogen-Activated Protein Kinase 9; D046988:Proteasome Endopeptidase Complex