c-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial Sab protein expression in mice
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
SAB is a mitochondrial scaffold protein linked to JNK-mediated ROS generation and acetaminophen-induced liver injury, and it is also a JNK substrate.
“SAB is a more recently identified scaffold protein localized to the mitochondria, accounting for JNK-mediated ROS generation (Chambers and LoGrasso, 2011), and acetaminophen-induced liver injury (Win et al., 2011), and is also a JNK substrate.”
From Structural Mechanisms of Allostery and Autoinhibition in JNK Family Kinases (2012) · cites this paper as Win et al., 2011
Activated p-JNK is known to translocate to mitochondria to initiate MPT change and damage following exposure to hepatotoxic agents including APAP.
“In addition, activated p-JNK is known to translocate to mitochondria to initiate MPT change and damage following exposure to hepatotoxic agents including APAP [115], [116], [130], [131].”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 40 · Cited by 197
Research works printed but not linked: 2
- Wiltshire, C., Gillespie, D. A., and May, G. H. (2004) Biochem. Soc. Trans. 32, 1075-1077
- Dahlin, D. C., Miwa, G. T., Lu, A. Y., and Nelson, S. D. (1984) Proc. Natl. Acad. Sci. U.S.A. 81, 1327-1331
- Authors
- Win, S., Than, T. A., Han, D., Petrovic, L. M., & Kaplowitz, N.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Kaplowitz, Neil
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 286
- Issue
- 40
- Pages
- 35071-35078
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC3186406
- OpenAlex
- W1972465938
- Cited by
- 197
- References
- 40
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 15 · 2023: 7 · 2022: 11 · 2021: 10 · 2020: 16 · 2019: 12 · 2018: 15 · 2017: 17 · 2016: 18 · 2015: 17 · 2014: 17 · 2013: 20 · 2012: 7
- FWCI
- 15.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Southern California (DK48522)
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (K01AA016911)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK067215, DK067215, P30DK048522)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- c-Jun N-terminal kinase, hepatotoxicity, paracetamol, TNF-α, MKK4, MAPK signaling, liver injury, hepatocytes
- MeSH terms
- Acetaminophen, Adenoviridae, Animals, Gene Expression Regulation, Glutathione, Liver, Male, Membrane Proteins, Mice, Inbred C57BL, Mitochondria, Tumor Necrosis Factor-alpha, Signal Transduction, Analgesics, Non-Narcotic, Hepatocytes, Mitochondrial Proteins, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
