A Conserved 3′UTR Stem–loop Directs UPF1/eIF4AIII-Dependent Regulation of GABARAPL1 mRNA
Year: 2026
Type: article
Abstract: RNA-binding proteins (RBP) interact with mRNA untranslated regions containing cis-regulatory elements to govern mRNA localization, stability, and translational efficiency. Among these trans-regulatory factors, RNA helicase UPF1 is a central factor which play a role in multiple mRNA decay pathways, including nonsense-mediated mRNA decay (NMD). NMD is triggered when an exon-junction complex (EJC) is located downstream of a premature termination codon. However, in some cases, NMD can be activated in an EJC-independent manner through mechanisms involving the 3'UTR. In the present study, we focused on the GABARAPL1 3'UTR, as previous studies had shown that this region plays a key role in NMD targeting, although the underlying molecular mechanism had not yet been elucidated. Unlike canonical NMD targets such as SC35, we found that the chemical inhibition of eIF4AIII helicase activity did not affect GABARAPL1 transcript levels, indicating that this transcript is regulated through its 3'UTR via an EJC-independent mechanism. We therefore investigated the potential presence of cis-regulatory element within the 3'UTR of GABARAPL1 which can regulate mRNA and protein levels in a UPF1-dependent manner. Furthermore, we identified a conserved RNA region spanning nucleotides 364-421 involved in GABARAPL1 targeting and used biochemical analysis to demonstrate the direct binding of UPF1 and eIF4AIII to this RNA region, to analyse its secondary structure in solution, and to map the protein-binding sites. By complementing these approaches with molecular modelling, we showed that this stem-loop adopts a stable global fold but a local flexibility and dynamic behaviour properties. Together, our results support the role of UPF1 and eIF4AIII as specific regulators of GABARAPL1 transcript and reveal a novel RNA regulatory element within its 3'UTR, which provides a completely unexpected binding site for these factors.
Source: Journal of Molecular Biology
Authors: Chloé Mercier, Maëlys Baudin, Francesca Fiorini, Cécilia Hognon, Jules Durand, Valérie Perez, Anne Peigney, Isabelle Lebars, Éric Hervouet, Paul Peixoto, Régis Delage-Mourroux, Annick Fraichard, Michaël Guittaut, Aurélie Baguet
Institutions: Inserm, Université Marie et Louis Pasteur, Interactions Hôte-Greffon-Tumeur & Ingénierie Cellulaire et Génique, Lyon 1 Université, Centre National de la Recherche Scientifique, Microbiologie moléculaire et biochimie structurale, Architecture et Réactivité de l'arN, Institut de Biologie Moléculaire et Cellulaire, Université de Strasbourg
Language: English
Topic: RNA Research and Splicing
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,730
Funders: Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Agence Nationale de Recherches sur le Sida et les Hépatites Virales, Ligue Contre le Cancer, Ministère de l'Education Nationale, de l'Enseignement Superieur et de la Recherche, Centre National de la Recherche Scientifique, Conseil régional de Bourgogne-Franche-Comté
Awards: G1512562798, G1708909202, G2763266775
OpenAlex ID: W4417458552