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The PIN domain of SMG-5 functionally interacts with SMG-6 to stimulate NMD

Matthew S Modena1, Chloe M Wohlenberg1, Marcus J Viscardi1

  • 1Department of MCD Biology, University of California at Santa Cruz, Santa Cruz, California 95064, USA.

RNA (New York, N.Y.)
|February 4, 2026
PubMed

Insights

Nonsense-Mediated mRNA Decay (NMD) relies on SMG-5 and SMG-6 protein interaction. This study reveals SMG-5

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Nonsense-Mediated mRNA Decay (NMD) is a crucial cellular pathway that degrades aberrant mRNAs containing premature stop codons, preventing the production of truncated proteins.
  • The precise molecular mechanisms of mRNA decay during NMD, particularly the roles of key factors like SMG-5 and SMG-6, remain incompletely understood.
  • SMG-6 is an endonuclease responsible for mRNA cleavage in NMD, and its activity has been observed to depend on the presence of SMG-5.

Purpose of the Study:

  • To elucidate the molecular basis for SMG-5's requirement in SMG-6-mediated mRNA cleavage within the NMD pathway.
  • To investigate the functional significance of the catalytically inactive PIN nuclease domain of SMG-5 in NMD.
  • To explore the interaction between SMG-5 and SMG-6 and its role in regulating mRNA decay.

Main Methods:

  • Utilized computational modeling with AlphaFold to predict interactions between SMG-5 and SMG-6 PIN domains.
  • Performed in vitro pulldown assays to experimentally validate the predicted SMG-5 and SMG-6 interaction.
  • Designed and introduced specific point mutations in C. elegans to disrupt and restore NMD function, guided by in silico models.

Main Results:

  • Demonstrated that conserved residues within the SMG-5 PIN domain, despite its lack of canonical active site residues, are essential for NMD.
  • Confirmed a direct interaction between the PIN domains of SMG-5 and SMG-6 through in vitro pulldown experiments.
  • Showcased that targeted point mutations, designed based on predicted interactions, can modulate NMD function in vivo, with compensatory mutations restoring activity.

Conclusions:

  • SMG-5 and SMG-6 interact to form a functional complex essential for NMD-mediated mRNA cleavage.
  • The PIN domain of SMG-5, previously considered inactive, plays a critical role in NMD, likely by facilitating SMG-6 activity.
  • This research provides novel insights into the molecular mechanisms of mRNA decay during NMD and highlights the functional importance of the SMG-5 PIN domain.
Keywords:
AlphaFoldC. elegansPIN domainSMG-5SMG-6nonsense-mediated mRNA decay

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