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E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure protein translation fidelity during neuronal development

ABSTRACT: The Leigh syndrome is a severe inborn neurodegenerative encephalopathy that is commonly associated with pyruvate metabolism defects. The transcription factor E4F1, a key regulator of the pyruvate dehydrogenase complex (PDC), was previously found to be mutated in Leigh syndrome patients but the molecular mechanisms leading to cell death in E4F1-deficient neurons remain unknown. Here, we show that E4F1 coordinates a transcriptional program involved in AcetylCoenzyme A (AcCoA) production by the PDC and its utilization by the Elongator complex to acetylate tRNAs and thereby enhance protein translation fidelity in the central nervous system. E4F1 directly regulates the expression of Dlat and Elp3, two genes encoding key subunits of the PDC and the Elongator complex. Consistently, genetic inactivation of E4f1 in neurons during mouse embryonic development decreased the activity of the PDC and of the Elongator complex, resulting in impaired tRNAs editing and the induction of an endoplasmic reticulum (ER) stress / unfolded protein response (UPR) that led to neuronal cell death and microcephaly. Impaired expression of ELP3 and activation of an ATF-driven UPR response was also observed in fibroblasts from Leigh syndrome patients harboring a homozygous E4F1K144Q mutation. Our findings identify a novel crosstalk between pyruvate metabolism and the regulation of protein translation that is perturbed in Leigh syndrome patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE158595 | GEO | 2022/12/20

REPOSITORIES: GEO

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Project description:Cancer genomics has illuminated a wide spectrum of genes and core molecular processes contributing to human malignancy. Still, the genetic and molecular basis of many cancers remains only partially explained. Genetic predisposition accounts for 5-10% of cancer diagnoses and genetic events cooperating with known somatic driver events are poorly understood. Analyzing established cancer predisposition genes in medulloblastoma (MB), a malignant childhood brain tumor, we recently identified pathogenic germline variants that account for 5% of all MB patients. Here, by extending our previous analysis to include all protein-coding genes, we discovered and replicated rare germline loss-of-function (LoF) variants across Elongator Complex Protein 1 (ELP1) on 9q31.3 in 15% of pediatric MBSHH cases, thus implicating ELP1 as the most common MB predisposition gene and increasing genetic predisposition to 40% for pediatric MBSHH. Inheritance was verified based on parent-offspring and pedigree analysis, which identified two families with a history of pediatric MB. ELP1-associated MBs were restricted to the molecular SHH subtype and were characterized by universal biallelic inactivation of ELP1 due to somatic loss of chromosome 9q. The majority of ELP1-associated MBs exhibited co-occurring somatic PTCH1 (9q22.32) alterations, suggesting that ELP1-deficiency predisposes to tumor development in combination with constitutive activation of SHH signaling. ELP1 is an essential subunit of the evolutionary conserved Elongator complex, whose primary function is to enable efficient translational elongation through tRNAs modifications at the wobble (U34) position. Biochemical, transcriptional, and proteomic analyses revealed that ELP1-associated MBSHH are characterized by a destabilized core Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response (UPR), consistent with deregulation of protein homeostasis due to Elongator-deficiency in model systems. Our findings suggest that genetic predisposition to proteome instability is a previously underappreciated determinant in the pathogenesis of pediatric brain cancer. These results provide strong rationale for further investigating the role of protein homeostasis in other pediatric and adult cancer types and potential opportunities for novel therapeutic interference.

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E4F1 coordinates pyruvate metabolism and the activity of the elongator complex to ensure protein translation fidelity during neuronal development

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