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Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag
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Rab10 Phosphorylation Detection by LRRK2 Activity Using SDS-PAGE with a Phosphate-binding Tag

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CASM mediates LRRK2 recruitment and activation under lysosomal stress

Tomoki Kuwahara1, Takeshi Iwatsubo1

  • 1Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Autophagy
|March 18, 2024
PubMed

Insights

Conjugation of ATG8 to single membranes (CASM) activates LRRK2 kinase, a protein linked to Parkinson disease. This process helps cells respond to lysosomal stress by altering lysosome shape and promoting secretion.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • The Atg8-family protein conjugation system has non-autophagic roles, including Conjugation of ATG8 to single membranes (CASM) at endolysosomal compartments.
  • The V-ATPase-ATG16L1 axis is a key mechanism regulating CASM.

Purpose of the Study:

  • To investigate the role of the V-ATPase-ATG16L1 axis in the non-autophagic function of ATG8 conjugation.
  • To elucidate the connection between CASM, lysosomal stress, and the Parkinson disease-associated kinase LRRK2.

Main Methods:

  • Investigated the V-ATPase-ATG16L1 axis in CASM.
  • Examined the recruitment and activation of LRRK2 at lysosomes under CASM conditions.
  • Assessed the impact of activated LRRK2 on lysosomal morphology and secretion.

Main Results:

  • The V-ATPase-ATG16L1 axis mediates CASM at endolysosomal compartments.
  • CASM induces lysosomal recruitment and activation of LRRK2.
  • Activated LRRK2 regulates lysosomal morphology and stimulates extracellular secretion of lysosomal contents.

Conclusions:

  • CASM is a non-autophagic function of the ATG8 system involving the V-ATPase-ATG16L1 axis.
  • This mechanism links lysosomal stress to LRRK2 activation, influencing cellular responses and potentially Parkinson disease pathogenesis.
Keywords:
ATG8 conjugation systemCASMLAPLRRK2V-ATPase-ATG16L1 axislysosome

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