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

Biochem Biophys Res Commun. 2021 Jun 25:559:230-237. doi: 10.1016/j.bbrc.2021.04.027. Epub 2021 May 4.

Abstract

MicroRNA (miRNA)-mediated translational suppression of mRNAs is involved in the regulation of multiple cellular processes. A recent study showed that Nup358, a protein mutated in a neurological disorder called acute necrotizing encephalopathy 1 (ANE1), helps in the coupling of miRNA-induced silencing complex (miRISC) - consisting of miRNA, AGO and GW182/TNRC6 proteins - with the target mRNA. Here we provide a detailed characterization of the interaction between Nup358 and GW182. We identified that the N-terminal region of Nup358 directly interacts with the C-terminal silencing domain of GW182. Interestingly, ANE1-associated Nup358 mutants display reduced interaction with GW182. Consistent with this, one of the prevalent ANE1 mutations, 585th threonine (T) residue changed to methionine (M) [T585M] compromised Nup358's ability to function in the miRNA pathway. Collectively, these results suggest that the ANE1-associated mutations in Nup358 might affect the miRNA pathway and contribute to the development of ANE1.

Keywords: ANE1; CNOT complex; Nucleoporin; Phase-separation; Translation; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantigens / chemistry
  • Autoantigens / metabolism*
  • Brain Diseases / genetics*
  • Cell Line
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Molecular Chaperones / metabolism*
  • Mutation / genetics*
  • Nuclear Pore Complex Proteins / metabolism*
  • Protein Binding
  • Protein Domains
  • RNA-Binding Proteins / chemistry
  • RNA-Binding Proteins / metabolism*

Substances

  • Autoantigens
  • MicroRNAs
  • Molecular Chaperones
  • Nuclear Pore Complex Proteins
  • RNA-Binding Proteins
  • TNRC6A protein, human
  • ran-binding protein 2