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NMD is required for timely cell fate transitions by fine-tuning gene expression and regulating translation.

ABSTRACT: Cell fate transitions depend on balanced rewiring of transcription and translation programs to mediate ordered developmental progression. Components of the nonsense-mediated mRNA decay (NMD) pathway have been implicated in regulating embryonic stem cell (ESC) differentiation, but the exact mechanism is unclear. Here we show that NMD controls expression levels of the translation initiation factor Eif4a2 and its premature termination codon-encoding isoform (Eif4a2 ^PTC ). NMD deficiency leads to translation of the truncated eIF4A2^PTC protein. eIF4A2^PTC elicits increased mTORC1 activity and translation rates and causes differentiation delays. This establishes a previously unknown feedback loop between NMD and translation initiation. Furthermore, our results show a clear hierarchy in the severity of target deregulation and differentiation phenotypes between NMD effector KOs (Smg5 KO > Smg6 KO > Smg7 KO), which highlights heterodimer-independent functions for SMG5 and SMG7. Together, our findings expose an intricate link between mRNA homeostasis and mTORC1 activity that must be maintained for normal dynamics of cell state transitions.

SUBMITTER: Huth M

PROVIDER: S-EPMC8973849 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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NMD is required for timely cell fate transitions by fine-tuning gene expression and regulating translation.

Huth Michelle M Santini Laura L Galimberti Elena E Ramesmayer Julia J Titz-Teixeira Fabian F Sehlke Robert R Oberhuemer Michael M Stummer Sarah S Herzog Veronika V Garmhausen Marius M Romeike Merrit M Chugunova Anastasia A Leesch Friederike F Holcik Laurenz L Weipoltshammer Klara K Lackner Andreas A Schoefer Christian C von Haeseler Arndt A Buecker Christa C Pauli Andrea A Ameres Stefan L SL Smith Austin A Beyer Andreas A Leeb Martin M

Genes & development 20220303 5-6

Cell fate transitions depend on balanced rewiring of transcription and translation programs to mediate ordered developmental progression. Components of the nonsense-mediated mRNA decay (NMD) pathway have been implicated in regulating embryonic stem cell (ESC) differentiation, but the exact mechanism is unclear. Here we show that NMD controls expression levels of the translation initiation factor Eif4a2 and its premature termination codon-encoding isoform (Eif4a2PTC</sup ...[more]

PMID: 35241478

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Project description:RationalePGC1α (peroxisome proliferator-activated receptor gamma coactivator 1α) represents an attractive target interfering bioenergetics and mitochondrial homeostasis, yet multiple attempts have failed to upregulate PGC1α expression as a therapy, for instance, causing cardiomyopathy.ObjectiveTo determine whether a fine-tuning of PGC1α expression is essential for cardiac homeostasis in a context-dependent manner.Methods and resultsModerate cardiac-specific PGC1α overexpression through a ROSA26 locus knock-in strategy was utilized in WT (wild type) mice and in G3Terc-/- (third generation of telomerase deficient; hereafter as G3) mouse model, respectively. Ultrastructure, mitochondrial stress, echocardiographic, and a variety of biological approaches were applied to assess mitochondrial physiology and cardiac function. While WT mice showed a relatively consistent PGC1α expression from 3 to 12 months old, age-matched G3 mice exhibited declined PGC1α expression and compromised mitochondrial function. Cardiac-specific overexpression of PGC1α (PGC1αOE) promoted mitochondrial and cardiac function in 3-month-old WT mice but accelerated cardiac aging and significantly shortened life span in 12-month-old WT mice because of increased mitochondrial damage and reactive oxygen species insult. In contrast, cardiac-specific PGC1α knock in in G3 (G3 PGC1αOE) mice restored mitochondrial homeostasis and attenuated senescence-associated secretory phenotypes, thereby preserving cardiac performance with age and extending health span. Mechanistically, age-dependent defect in mitophagy is associated with accumulation of damaged mitochondria that leads to cardiac impairment and premature death in 12-month-old WT PGC1αOE mice. In the context of telomere dysfunction, PGC1α induction replenished energy supply through restoring the compromised mitochondrial biogenesis and thus is beneficial to old G3 heart.ConclusionsFine-tuning the expression of PGC1α is crucial for the cardiac homeostasis because the balance between mitochondrial biogenesis and clearance is vital for regulating mitochondrial function and homeostasis. These results reinforce the importance of carefully evaluating the PGC1α-boosting strategies in a context-dependent manner to facilitate clinical translation of novel cardioprotective therapies.

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NMD is required for timely cell fate transitions by fine-tuning gene expression and regulating translation.

Publications

NMD is required for timely cell fate transitions by fine-tuning gene expression and regulating translation.

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