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The Vsr-like protein FASTKD4 regulates the stability and polyadenylation of the MT-ND3 mRNA

Xuan Yang1, Maike Stentenbach2,3, Laetitia A Hughes2,3

  • 1Department of Molecular Cell Biology, University of Geneva, Quai Ernest-Ansermet 30, 1211 Geneva, Switzerland.

Nucleic Acids Research
|December 27, 2024
PubMed

Insights

Mitochondrial RNA-binding proteins (RBPs) regulate gene expression. Researchers studied FASTKD4, revealing its role in MT-ND3 mRNA maturation and translation via poly(A) tail binding, crucial for mitochondrial function.

Area of Science:

  • Molecular Biology
  • Mitochondrial Biology
  • RNA Metabolism

Background:

  • Nuclear-encoded RNA-binding proteins (RBPs) regulate mitochondrial gene expression.
  • The Fas-activated serine/threonine kinase (FASTK) family fine-tunes mitochondrial RNA processing, maturation, stability, and translation.
  • The precise molecular mechanisms of FASTK proteins in mitochondrial RNA metabolism are not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanisms of FASTKD4 in mitochondrial RNA metabolism.
  • To determine the structural basis for FASTKD4's function.
  • To investigate the role of FASTKD4 in MT-ND3 mRNA maturation and translation.

Main Methods:

  • X-ray crystallography to resolve the atomic structure of FASTKD4.
  • Biochemical assays to study FASTKD4's RNA-binding activity.
  • Cellular studies to assess the impact of FASTKD4 loss on mitochondrial gene expression.

Main Results:

  • The atomic structure of FASTKD4 revealed a positively charged cavity, similar to very short patch repair endonucleases.
  • FASTKD4 directly binds the poly(A) tail of MT-ND3 mRNA, facilitating its maturation and translation.
  • Loss of FASTKD4 in cells leads to reduced MT-ND3 polyadenylation and mRNA destabilization.

Conclusions:

  • FASTKD4 plays a critical role in the maturation and translation of MT-ND3 mRNA.
  • The structural and biochemical data provide mechanistic insights into FASTKD4 function.
  • Dysregulation of FASTKD4 impacts mitochondrial gene expression and mRNA stability.

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