title: c-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial Sab protein expression in mice.
abstract: Sustained JNK activation plays a critical role in hepatotoxicity by acetaminophen or GalN/TNF-α. To address the importance of JNK translocation to mitochondria that accompanies sustained activation in these models, we assessed the importance of the expression of a potential initial target of JNK in the outer membrane of mitochondria, namely Sab (SH3 domain-binding protein that preferentially associates with Btk), also known as Sh3bp5 (SH3 domain-binding protein 5). Silencing the expression of Sab in the liver using adenoviral shRNA inhibited sustained JNK activation and mitochondrial targeting of JNK and the upstream MKK4 (MAPK kinase 4), accompanied by striking protection against liver injury in vivo and in cultured hepatocytes in both toxicity models. We conclude that mitochondrial Sab may serve as a platform for the MAPK pathway enzymes and that the interaction of stress-activated JNK with Sab is required for sustained JNK activation and toxicity.
authors.affiliation: Division of Gastrointestinal and Liver Diseases, University of Southern California Research Center for Liver Diseases, University of Southern California, Los Angeles, California 90089-9121, USA.
authors.forename: Sanda
authors.initials: S
authors.lastname: Win
authors.forename: Tin Aung
authors.initials: TA
authors.lastname: Than
authors.forename: Derick
authors.initials: D
authors.lastname: Han
authors.forename: Lydia M
authors.initials: LM
authors.lastname: Petrovic
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000256:Adenoviridae / Q000378:metabolism; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D005786:Gene Expression Regulation; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000293:injuries*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D018712:Analgesics, Non-Narcotic; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C568472:Sab protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000082:Acetaminophen; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C482562:Map2k4 protein, mouse; D005978:Glutathione