The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes

ELife
Yao Liang WongCarmela Sidrauski

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 (<xref ref-type="bibr" rid="bib38">Sidrauski et al., 2015</xref>). 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.

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Methods Mentioned

BETA
nucleotide
GTPase
light scattering
size-exclusion chromatography
PCR

Software Mentioned

Prism
GraphPad
ImageJ
ISRIB
ClinVar

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