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Acute necrotizing encephalopathy-linked mutations in Nup358 impair interaction of Nup358 with TNRC6/GW182 and miRNA

Prachi Deshmukh1, Aditi Singh1, Deepak Khuperkar1

  • 1National Centre for Cell Science, S.P. Pune University Campus, Pune, 411007, India.

Biochemical and Biophysical Research Communications
|May 7, 2021
PubMed

Insights

Nup358 protein mutations linked to ANE1 neurological disorder impair its interaction with GW182, disrupting microRNA (miRNA) pathways crucial for cellular regulation.

Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • MicroRNA (miRNA)-mediated translational suppression regulates cellular processes.
  • Nup358 protein is implicated in acute necrotizing encephalopathy 1 (ANE1).
  • Nup358 facilitates the interaction between the miRNA-induced silencing complex (miRISC) and target mRNAs.

Purpose of the Study:

  • To characterize the interaction between Nup358 and GW182.
  • To investigate the impact of ANE1-associated Nup358 mutations on this interaction.
  • To understand how Nup358 dysfunction contributes to ANE1 pathogenesis.

Main Methods:

  • Protein interaction studies to map Nup358 and GW182 binding sites.
  • Analysis of Nup358 mutants associated with ANE1.
  • Functional assays assessing Nup358's role in the miRNA pathway.

Main Results:

  • The N-terminal region of Nup358 directly interacts with the C-terminal silencing domain of GW182.
  • ANE1-associated Nup358 mutants exhibit reduced binding affinity to GW182.
  • The T585M mutation in Nup358 significantly impairs its function in the miRNA pathway.

Conclusions:

  • Nup358 directly interacts with GW182, a key component of the miRISC.
  • Mutations in Nup358 found in ANE1 patients weaken this interaction.
  • Dysregulation of the miRNA pathway due to Nup358 mutations may contribute to ANE1 development.
Keywords:
ANE1CNOT complexNucleoporinPhase-separationTranslationmiRNA

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