Structure of the Nmd4-Upf1 complex supports conservation of the nonsense-mediated mRNA decay pathway between yeast and humans

Irène Barbarin-Bocahu; Nathalie Ulryck; Amandine Rigobert; Nadia Ruiz Gutierrez; Laurence Decourty; Mouna Raji; Bhumika Garkhal; Hervé Le Hir; Cosmin Saveanu; Marc Graille

doi:10.1371/journal.pbio.3002821

Structure of the Nmd4-Upf1 complex supports conservation of the nonsense-mediated mRNA decay pathway between yeast and humans

PLoS Biol. 2024 Sep 27;22(9):e3002821. doi: 10.1371/journal.pbio.3002821. eCollection 2024 Sep.

Affiliations

¹ Laboratoire de Biologie Structurale de la Cellule (BIOC), CNRS, Ecole polytechnique, Institut Polytechnique de Paris, Palaiseau, France.
² Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, Paris, France.
³ Institut Pasteur, Université Paris Cité, Unité Biologie des ARN des Pathogènes Fongiques, Paris, France.

Abstract

The nonsense-mediated mRNA decay (NMD) pathway clears eukaryotic cells of mRNAs containing premature termination codons (PTCs) or normal stop codons located in specific contexts. It therefore plays an important role in gene expression regulation. The precise molecular mechanism of the NMD pathway has long been considered to differ substantially from yeast to metazoa, despite the involvement of universally conserved factors such as the central ATP-dependent RNA-helicase Upf1. Here, we describe the crystal structure of the yeast Upf1 bound to its recently identified but yet uncharacterized partner Nmd4, show that Nmd4 stimulates Upf1 ATPase activity and that this interaction contributes to the elimination of NMD substrates. We also demonstrate that a region of Nmd4 critical for the interaction with Upf1 in yeast is conserved in the metazoan SMG6 protein, another major NMD factor. We show that this conserved region is involved in the interaction of SMG6 with UPF1 and that mutations in this region affect the levels of endogenous human NMD substrates. Our results support the universal conservation of the NMD mechanism in eukaryotes.

Copyright: © 2024 Barbarin-Bocahu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

MeSH terms

Adenosine Triphosphatases / genetics
Adenosine Triphosphatases / metabolism
Crystallography, X-Ray
Endoribonucleases
Humans
Nonsense Mediated mRNA Decay*
Protein Binding
RNA Helicases* / genetics
RNA Helicases* / metabolism
RNA, Messenger / genetics
RNA, Messenger / metabolism
Saccharomyces cerevisiae Proteins* / genetics
Saccharomyces cerevisiae Proteins* / metabolism
Saccharomyces cerevisiae* / genetics
Saccharomyces cerevisiae* / metabolism
Trans-Activators / genetics
Trans-Activators / metabolism

Substances

Saccharomyces cerevisiae Proteins
RNA Helicases
NAM7 protein, S cerevisiae
UPF1 protein, human
SMG6 protein, human
RNA, Messenger
Trans-Activators
Adenosine Triphosphatases
Endoribonucleases

Grants and funding

This work was supported by the Centre National de la Recherche Scientifique (CNRS) to HLH and MG, the Ecole Normale Supérieure and the Institut National de la Santé et de la Recherche Médicale for HLH, Institut Pasteur to CS, the Agence Nationale pour la Recherche ANR-18-CE11-0003-01 to CS, ANR-18-CE11-0003-02 and ANR-22-CE12-0004 to HLH and ANR-18-CE11-0003-04 to MG, Ecole Polytechnique to MG, the French Ministère de l’Enseignement Supérieur et de la Recherche (MESR) to IBB/BG, Ecole doctorale Complexité du Vivant (ED 515, Sorbonne Université) for PhD funding of NRG and the Fondation ARC pour la Recherche sur le Cancer for PhD funding of NRG and IBB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.