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Post-Translational Modifications of the DUX4 Protein Impact Toxic Function in FSHD Cell Models.

Renatta N Knox1, Jocelyn O Eidahl2, Lindsay M Wallace2

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Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder characterized by progressive muscle weakness.
  • The disease is primarily caused by the aberrant expression of the double-homeobox 4 (DUX4) gene.
  • While DUX4's transcriptional targets are known, its protein regulation and downstream effects remain incompletely understood.

Purpose of the Study:

  • To investigate the post-translational modifications (PTMs) of the DUX4 protein.
  • To characterize how these PTMs impact DUX4's toxic function in FSHD.
  • To identify potential enzyme modifiers regulating DUX4 PTMs.

Main Methods:

  • Utilized in vitro FSHD models, including HEK293 and human myoblast cell lines.
  • Employed immunoprecipitation and mass spectrometry to identify DUX4 PTMs.
  • Performed mutagenesis, proteomics, and biochemical assays to characterize PTMs and enzyme interactions.

Main Results:

  • Identified 17 DUX4 amino acids with PTMs and created 55 DUX4 mutants.
  • Demonstrated that specific DUX4 mutants reduced DUX4-mediated toxicity and biomarker transactivation.
  • Found that serine/threonine phosphorylation and arginine methylation inhibition counteract DUX4 toxicity.
  • Confirmed interactions between DUX4 and key enzymes: protein kinase A (PKA) and protein arginine methyltransferase 1 (PRMT1).

Conclusions:

  • DUX4 protein is subject to significant post-translational modifications.
  • These PTMs play a crucial role in regulating DUX4's toxic activity in FSHD.
  • DUX4 PTMs and their modifying enzymes represent promising targets for novel FSHD therapeutic strategies.