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ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission

Palamou Das1,2, Oishee Chakrabarti3,4

  • 1Biophysics & Structural Genomics Division, Saha Institute of Nuclear Physics, 1/AF Bidhannagar, Kolkata, 700064, India.

Cell Death & Disease
|March 2, 2024
PubMed

Insights

Interferon-stimulated gene 15 (ISG15) modifies dynamin-related protein 1 (DRP1), promoting mitochondrial fission. This novel DRP1 ISGylation impacts mitochondrial dynamics and may be relevant to Alzheimer's disease.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Neuroscience

Background:

  • Dynamin-related protein 1 (DRP1) is crucial for mitochondrial fission.
  • DRP1 undergoes various post-translational modifications.
  • Mitochondrial dynamics are implicated in neurodegenerative diseases.

Purpose of the Study:

  • To identify novel post-translational modifications of DRP1.
  • To investigate the role of ISG15 in DRP1 function and mitochondrial dynamics.
  • To explore the implications of DRP1 ISGylation in Alzheimer's disease.

Main Methods:

  • Identified ISGylation of DRP1 mediated by HERC5.
  • Observed effects of deISGylation using SARS-CoV2 PLpro.
  • Analyzed DRP1 ubiquitylation and degradation pathways.
  • Investigated the interplay between DRP1 phosphorylation and ISGylation.

Main Results:

  • DRP1 ISGylation by HERC5 promotes mitochondrial fission.
  • DeISGylation of DRP1 leads to mitochondrial hyperfusion.
  • DeISGylated DRP1 is degraded by TRIM25.
  • ISGylation of phospho-DRP1 (S616) enhances mitochondrial fission competence.

Conclusions:

  • ISGylation is a novel regulator of DRP1 function and mitochondrial dynamics.
  • DRP1 ISGylation impacts mitochondrial morphology and is linked to Alzheimer's disease pathophysiology.
  • This finding reveals a new layer of regulation for DRP1 in cellular processes.

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