Wester, L. | Search bioRxiv

bioRxiv2020

eIF2B extends lifespan through inhibition of the integrated stress response

Protein homeostasis is modulated by stress response pathways and its deficiency is a hallmark of aging. The integrated stress response (ISR) is a conserved stress-signaling pathway that tunes mRNA translation via phosphorylation of the translation initiation factor eIF2. ISR activation and translation initiation are finely balanced by eIF2 kinases and by the eIF2 guanine nucleotide exchange factor eIF2B. However, the role of the ISR during aging remains unexplored. Using a genomic screen in Caenorhabditis elegans, we discovered a role of eIF2B and the eIF2 kinases in longevity. By limiting the ISR, these mutations enhanced protein homeostasis and increased lifespan. Consistently, full ISR inhibition using phosphorylation-defective eIF2 or pharmacological ISR inhibition prolonged lifespan. Lifespan extension through ISR inhibition occurred without changes in overall protein synthesis, and depended on enhanced translational efficiency of the kinase KIN-35. Evidently, lifespan is limited by the ISR and its inhibition may provide an intervention in aging.

genetics↗

bioRxiv2019

5’ tRNA halves are highly expressed in the primate hippocampus and sequence-specifically regulate gene expression

Fragments of mature tRNAs have long been considered as mere degradation products without physiological function. However, recent reports show that tRNA fragments (tRFs) play prominent roles in diverse cellular processes across a wide spectrum of species. Contrasting the situation in other small RNA pathways the mechanisms behind these effects appear more diverse, more complex and are generally less well understood. In addition, surprisingly little is known about the expression profiles of tRFs across different tissues and species. Here, we provide an initial overview of tRF expression in different species and tissues, revealing very high tRF-levels particularly in the primate hippocampus. We further modulated the regulation capacity of selected tRFs in human cells by transfecting synthetic tRF mimics (\"overexpression\") or antisense-RNAs (\"inhibition\") and identified differentially expressed transcripts based on RNAseq. We then used a novel k-mer mapping approach to dissect the underlying targeting rules, demonstrating that 5 tRNA halves (5 tRHs) silence genes in a sequence-specific manner, while the most efficient target sites align to the mid-region of the 5 tRH and are located within the CDS or 3 UTR of the target. This amends previous observations that tRFs guide Argonaut proteins to silence their targets via a miRNA-like 5 seed match and suggests a yet unknown mechanism of regulation. Finally, our data suggests that some 5 tRHs are also able to sequence-specifically stabilize mRNAs as upregulated mRNAs are also significantly enriched for 5 tRH target sites.

molecular biology↗