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Updated: Oct 6, 2025

Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation
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Lighting Up the Pathways to Caspase Activation Using Bimolecular Fluorescence Complementation

Published on: March 5, 2018

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Cellular autophagy, an unbidden effect of caspase inhibition by zVAD-fmk

Dharaniya Sakthivel1,2,3, Beatriz E Bolívar2,3, Lisa Bouchier-Hayes2,3,4

  • 1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

The FEBS Journal
|January 19, 2022
PubMed

Insights

The pan-caspase inhibitor zVAD-fmk induces autophagy by inhibiting N-glycanase NGLY1, not caspases. This finding reveals a link between protein turnover and autophagy, crucial for understanding NGLY1-related disorders.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Background:

  • The pan-caspase inhibitor zVAD-fmk is commonly used to block apoptosis.
  • zVAD-fmk has known side effects, including the induction of autophagy.
  • The precise mechanism by which zVAD-fmk induces autophagy remains unclear.

Purpose of the Study:

  • To investigate the mechanism by which zVAD-fmk induces autophagy.
  • To determine if N-glycanase NGLY1 is involved in zVAD-fmk-induced autophagy.
  • To explore the relationship between NGLY1, protein turnover, and autophagy.

Main Methods:

  • Utilizing chemical inhibitors and genetic approaches to study cellular pathways.
  • Assessing the impact of zVAD-fmk on NGLY1 activity.
  • Analyzing the effects of NGLY1 inhibition on autophagy levels.

Main Results:

  • zVAD-fmk induces autophagy by inhibiting N-glycanase NGLY1.
  • NGLY1 inhibition, rather than caspase inhibition, is responsible for zVAD-fmk's autophagic side effect.
  • NGLY1 plays a role in regulating basal autophagy levels.

Conclusions:

  • The study identifies NGLY1 as a novel target mediating zVAD-fmk-induced autophagy.
  • This finding highlights potential crosstalk between protein turnover pathways and autophagy.
  • Emphasizes the importance of chemical tool specificity in biological research, particularly concerning NGLY1 and neurodevelopmental disorders.
Keywords:
NLGY1apoptosisautophagycaspasezVAD-fmk

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