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The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes
- Source :
- eLife, eLife, Vol 7 (2018)
- Publication Year :
- 2018
- Publisher :
- eLife Sciences Publications, Ltd, 2018.
-
Abstract
- eIF2B is a dedicated guanine nucleotide exchange factor for eIF2, the GTPase that is essential to initiate mRNA translation. The integrated stress response (ISR) signaling pathway inhibits eIF2B activity, attenuates global protein synthesis and upregulates a set of stress-response proteins. Partial loss-of-function mutations in eIF2B cause a neurodegenerative disorder called Vanishing White Matter Disease (VWMD). Previously, we showed that the small molecule ISRIB is a specific activator of eIF2B (Sidrauski et al., 2015). Here, we report that various VWMD mutations destabilize the decameric eIF2B holoenzyme and impair its enzymatic activity. ISRIB stabilizes VWMD mutant eIF2B in the decameric form and restores the residual catalytic activity to wild-type levels. Moreover, ISRIB blocks activation of the ISR in cells carrying these mutations. As such, ISRIB promises to be an invaluable tool in proof-of-concept studies aiming to ameliorate defects resulting from inappropriate or pathological activation of the ISR.
- Subjects :
- 0301 basic medicine
QH301-705.5
Science
Mutant
GTPase
Integrated Stress Response
translation initiation
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
0302 clinical medicine
Biochemistry and Chemical Biology
None
Integrated stress response
Biology (General)
eIF2
General Immunology and Microbiology
biology
Chemistry
Activator (genetics)
General Neuroscience
Cell Biology
General Medicine
Cell biology
Vanishing White Matter Disease
030104 developmental biology
eIF2B
biology.protein
Medicine
Guanine nucleotide exchange factor
Signal transduction
Research Advance
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 2050084X
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- eLife
- Accession number :
- edsair.doi.dedup.....9e1d41f30de84e37d6db028d886b0d04