Summary Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nrf2/Nfe2l2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine EGFR signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.
Cryptic polyadenylation within coding sequences (CDS) triggers ribosome-associated quality control (RQC), followed by degradation of the aberrant mRNA and polypeptide, ribosome disassembly and recycling. Although ribosomal subunit dissociation and nascent peptide degradation are well-understood, the molecular sensors of aberrant mRNAs and their mechanism of action remain unknown. We studied the Zinc Finger Protein 598 (ZNF598) using PAR-CLIP and revealed that it cross-links to tRNAs, mRNAs and rRNAs, thereby placing the protein on translating ribosomes. Cross-linked reads originating from AAA-decoding tRNALys(UUU) were 10-fold enriched over its cellular abundance, and poly-lysine encoded by poly(AAA) induced RQC in a ZNF598-dependent manner. Encounter with translated polyA segments by ZNF598 triggered ubiquitination of several ribosomal proteins, requiring the E2 ubiquitin ligase UBE2D3 to initiate RQC. Considering that human CDS are devoid of >4 consecutive AAA codons, sensing of prematurely placed polyA tails by a specialized RNA-binding protein is a novel nucleic-acid-based surveillance mechanism of RQC.
SUMMARYFragile X syndrome (FXS) is the leading genetic cause of autism. Mutations in Fmr1 (fragile X mental retardation 1 gene) engender exaggerated translation resulting in dendritic spine dysmorphogenesis, synaptic plasticity alterations, and behavioral deficits in mice, which are reminiscent of FXS pheno-types. Using postmortem brains from FXS patients and Fmr1 knockout mice (Fmr1 −/y), we show that phosphorylation of the mRNA 5′ cap binding protein, eukaryotic initiation factor 4E (eIF4E), is elevated concomitant with increased expression of matrix metalloproteinase 9 (MMP-9) protein. Genetic or pharmacological reduction of eIF4E phosphorylation rescued core behavioral deficits, synaptic plasticity alterations, and dendritic spine morphology defects via reducing exaggerated translation of Mmp9 mRNA in Fmr1 −/y mice, whereas MMP-9 overexpression produced several FXS-like phenotypes. These results uncover a mechanism of regulation of synaptic function by translational control of Mmp-9 in FXS, which opens the possibility of new treatment avenues for the diverse neurological and psychiatric aspects of FXS.
Fragile X syndrome is the leading monogenic cause of ASD. Trinucleotide repeats in the FMR1 gene abolish FMRP protein expression, leading to hyperactivation of ERK and mTOR signaling, upstream of mRNA translation. Here we show that metformin, the most widely used anti-type 2 diabetes drug, rescues core phenotypes in Fmr1-/y mice and selectively normalizes Erk signaling, Eif4e phosphorylation and the expression of Mmp9. Thus, metformin is a potential FXS therapeutic. Dysregulated mRNA translation is linked to core pathologies diagnosed in the Fragile X neurodevelopmental Syndrome (FXS), such as social and behavior problems, developmental delays and learning disabilities 1,2. In the brains of FXS patients and knockout mice (Fmr1-/y ; X-linked Fmr1 deletion in male mice), loss of Fragile X mental retardation protein (FMRP) results in hyperactivation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and the extracellular signal-regulated kinase (ERK) signaling pathways 1,2. Consistent with increased ERK activity, eukaryotic initiation factor 4E (eIF4E) phosphorylation is elevated in the brain of FXS patients and Fmr1-/y mice, thereby promoting translation of the mRNA encoding for matrix metalloproteinase 9 (MMP-9), which is elevated in the brains of both FXS patients and the Fmr1-/y mice 1-5. In accordance with these findings, knockout of Mmp9 rescues the majority of phenotypes in Fmr1-/y mice. MMP-9 degrades components of the extracellular matrix, including proteins important for synaptic function and maturation, which are implicated in FXS and autism spectrum disorders (ASD). Recent observations indicate that metformin, a first-line therapy for type 2 diabetes, imparts numerous health benefits beyond its original therapeutic use, such as decreased cancer risk and improved cancer prognosis 6. Metformin inhibits the mitochondrial respiratory chain complex 1, leading to a decrease in cellular energy state and thus activation of the energy sensor AMP-activated protein kinase (AMPK) 6. Several AMPK-independent activities of metformin have also been reported 7,8. Since metformin suppresses translation by inhibiting
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