Related Experiment Video

Updated: Oct 3, 2025

Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy
07:20

Exploring the Regulation of Lipid Droplet Catabolism through Lipophagy

Published on: January 31, 2025

692

A dominant-negative regulatory mechanism of SQSTM1 droplets-based autophagy

Evelina Valionyte1, Elizabeth R Barrow1, Chris R Baxter1

  • 1Peninsula Medical School, Faculty of Health, University of Plymouth, Plymouth, UK.

Autophagy
|February 21, 2022
PubMed

Insights

Inflammatory stress triggers CASP6 to cleave SQSTM1/p62, generating a fragment that inhibits droplet formation and impairs autophagy. This CASP6-SQSTM1 pathway negatively regulates cellular clearance mechanisms during stress.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Autophagy Research

Background:

  • Sequestosome 1 (SQSTM1/p62) acts as an autophagy receptor, forming liquid-like droplets to capture polyubiquitinated cargo for degradation.
  • These SQSTM1 droplets serve as platforms for autophagosome biogenesis, crucial for cellular waste removal.
  • The regulatory mechanisms governing SQSTM1 droplet formation remain incompletely understood.

Purpose of the Study:

  • To investigate the regulation of SQSTM1 droplet formation under stress conditions.
  • To identify how inflammatory toxicity impacts SQSTM1 function in autophagy.

Main Methods:

  • Investigated the cleavage of SQSTM1 by Caspase-6 (CASP6) at a newly identified site (D256) induced by inflammatory toxicity.
  • Analyzed the functional consequences of SQSTM1 cleavage products on droplet formation and autophagosome biogenesis.
  • Utilized cellular models to study the CASP6-SQSTM1 interaction and its role in autophagy regulation.

Main Results:

  • Inflammatory stress induces CASP6-mediated cleavage of SQSTM1 at D256.
  • The N-terminal fragment (SQSTM1-N) inhibits SQSTM1 droplet formation and impairs autophagosome assembly.
  • The C-terminal fragment is rapidly degraded and likely non-functional.

Conclusions:

  • The CASP6-SQSTM1 axis represents a novel negative regulatory mechanism for autophagy.
  • This pathway attenuates SQSTM1 droplet-dependent autophagosome formation under specific stress conditions.
  • Understanding this axis provides insights into cellular stress responses and autophagic flux control.
Keywords:
AutophagosomesCASP6SQSTM1autophagyliquid droplets

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