ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats.

By H. Nishitoh, A. Matsuzawa, K. Tobiume, K. Saegusa, K. Takeda, Kiyoshi Inoue, Seiji Hori, A. Kakizuka, H. Ichijo. Genes & Development, 2002

1,409 citations recorded by the source corpus.

Expansion of CAG trinucleotide repeats that encode polyglutamine is the underlying cause of at least nine inherited human neurodegenerative disorders, including Huntington's disease and spinocerebellar ataxias. PolyQ fragments accumulate as aggregates in the cytoplasm and/or in the nucleus, and induce neuronal cell death. However, the molecular mechanism of polyQ-induced cell death is controversial. Here, we show the following: (1) polyQ with pathogenic repeat length triggers ER stress through proteasomal dysfunction; (2) ER stress activates ASK 1 through formation of an IRE1-TRAF2-ASK1 complex; and (3) ASK1(-/-) primary neurons are defective in polyQ-, proteasome inhibitor-, and ER stress-induced JNK activation and cell death. These findings suggest that ASK1 is a key element in ER stress-induced cell death that plays an important role in the neuropathological alterations in polyQ diseases.

Subfields: Cell Biology, Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/35cc1d817f31b7d63295df1f7649bf1a0f191341

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In Cell Biology

1. R. Kaufman
2. J. Malhotra
3. D. Ron
4. G. Hotamışlıgil
5. Afshin Samali
6. A. Gorman
7. John Calvin Reed
8. Peter Walter

In Cellular and Molecular Neuroscience

1. R. Kaufman
2. J. Malhotra
3. Peter Walter
4. E. K. Kim
5. E. Choi
6. Hanna Wootz
7. L. Korhonen
8. D. Lindholm

In Molecular Biology

1. R. Kaufman
2. D. Ron
3. J. Malhotra
4. Afshin Samali
5. A. Gorman
6. Peter Walter
7. H. Harding
8. G. Hotamışlıgil

Citations in the corpus

• From acute ER stress to physiological roles of the Unfolded Protein Response (2006, background): “apoptosis by interaction with TRAF2 (TNF receptor-associated factor-2) and ASK1 leading to the activation of ASK1 and JNK, and subsequent cell death.(46) It has also been suggested that IRE1/TRAF2 association releases procas-”
• Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Cycle or a Double-Edged Sword? (2007, neutral): “Activated IRE1 re-cruits TRAF2 to elicit JNK phosphorylation and activation.”
• The endoplasmic reticulum is the site of cholesterol-induced cytotoxicity in macrophages (2003, background): “, Jun N -terminal stress-activated protein kinase”
• TRB3, a novel ER stress‐inducible gene, is induced via ATF4–CHOP pathway and is involved in cell death (2005, background): “High levels of sustained ER stress can result in apoptosis, and some of the factors controlling this response, the activation of c-Jun N-terminal kinase (JNK) (Nishitoh et al, 2002), the activation of caspase-12 (Nakagawa et al, 2000) and transcriptional induction of CHOP (Zinszner et al, 1998), hav”
• Mediators of endoplasmic reticulum stress‐induced apoptosis (2006, background): “Overexpression of ASK1 induced apoptosis in several cell types, whereas neurons from Ask1–/– mice exhibited resistance to lethal ER stress, illustrating the importance of ASK1 in ER stress-induced cell death (Hatai et al, 2000; Nishitoh et al, 2002).”
• Roles of CHOP/GADD153 in endoplasmic reticulum stress (2004, background): “MAPKKK ASK1, which is required for activation of JNK by Ire1 during ER stress, can also activate the p38 pathway.(19,55) ASK1 null cells are resistant to ER stress-induced apoptosis.”
• Endoplasmic reticulum stress signaling in disease. (2006, background): “Activated IRE1 recruits the scaffolding protein TRAF2 to the ER membrane (192), which triggers a mitogen-activated protein (MAP) kinase cascade leading to JNK activation (129, 130).”
• Cellular Stress Responses: Cell Survival and Cell Death (2010, background): “IRE1 also participates in ER stressinduced cell death by activating JNK through the binding with ASK1 and Traf2 [150, 151].”
• Endoplasmic Reticulum Stress and the Unfolded Protein Response in Cellular Models of Parkinson's Disease (2002, background): “These affect protein folding in the cytoplasm and may lead to ER stress by impacting the process of ER-associated protein degradation (Bence et al., 2001; Nishtoh et al., 2002).”
• Cell death and endoplasmic reticulum stress: disease relevance and therapeutic opportunities (2008, background): “Among other functions, IRE1 and TRAF2 collaborate to activate protein kinases that have previously been implicated in immunity, inflammation and apoptosis, in particular apoptosis signal-regulating kinase 1 (ASK1; also known as MAP3K5), which causes JNK activatio”
• ROS-dependent activation of the TRAF6-ASK1-p38 pathway is selectively required for TLR4-mediated innate immunity (2005, background): “ASK1, which is encoded by Map3k5 , activates the MAP kinase kinase 4 (MKK4)-Jnk and MKK7-Jnk and MKK3-p38 and MKK6-p38 pathways and it is pivotal in cytokine- and stress-induced apoptosis in mammalian cell”