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

Elife. 2018 Feb 28:7:e32733. doi: 10.7554/eLife.32733.


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.

Keywords: Integrated Stress Response; Vanishing White Matter Disease; biochemistry; cell biology; chemical biology; eIF2B; none; translation initiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / metabolism*
  • Cell Line
  • Cyclohexylamines / metabolism*
  • Enzyme Activators / metabolism*
  • Eukaryotic Initiation Factor-2B / genetics
  • Eukaryotic Initiation Factor-2B / metabolism*
  • Humans
  • Leukoencephalopathies / genetics
  • Leukoencephalopathies / physiopathology*
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism*
  • Neuroprotective Agents / metabolism*


  • 2-(4-chlorophenoxy)-N-(4-(2-(4-chlorophenoxy)acetamido)cyclohexyl)acetamide
  • Acetamides
  • Cyclohexylamines
  • Enzyme Activators
  • Eukaryotic Initiation Factor-2B
  • Mutant Proteins
  • Neuroprotective Agents

Grants and funding

This study was funded by Calico Life Sciences LLC.