Project description:We report RNA sequencing (RNA-seq) data WT, atf-4 loss-of-function mutants, and ATF-4 OE worms under non-stressed conditions. Three independent biological replicates were prepared for each sample, and worms were harvested at L4 stage.
Project description:To gain molecular insights into how ATF-4 regulates C. elegans defense against bacterial infection, we employed RNA-seq to profile gene expression in atf-4(ok576) and WT animals with or without S. enterica infection.
Project description:Functional crosstalk between organelles is critical for maintaining cellular homeostasis. Individually, dysfunction of both endoplasmic reticulum (ER) and mitochondria have been linked to cellular and organismal aging, but little is known about how mechanisms of inter-organelle communication might be targeted to extended longevity. The metazoan unfolded protein response (UPR) maintains ER health through a variety of mechanisms beyond its canonical role in proteostasis, including calcium storage and lipid metabolism. Here we provide evidence that in C. elegans, inhibition of the conserved UPR mediator, activating transcription factor (atf)-6 increases lifespan via modulation of calcium homeostasis and signaling to the mitochondria. Loss of atf-6 confers long life via downregulation of the ER calcium buffering protein, calreticulin. Function of the ER calcium release channel, the inositol triphosphate receptor (IP3R/itr-1), is required for atf-6 mutant longevity while a gain-of-function IP3R/itr-1 mutation is sufficient to extend lifespan. IP3R dysfunction leads to altered mitochondrial behavior and hyperfused morphology, which is sufficient to suppress long life in atf-6 mutants. Highlighting a novel and direct role for this inter-organelle coordination of calcium in longevity, the mitochondrial calcium import channel, mcu-1, is also required for atf-6 mutant longevity. Altogether this study reveals the importance of organellar coordination of calcium handling in determining the quality of aging, and highlights calcium homeostasis as a critical output for the UPR and atf-6 in particular.
Project description:The present study demonstrates that ATF-3 plays a tumor suppressing function in melanoma. Overexpression of ATF-3 in metastatic melanoma cell lines significantly inhibited their growth, migration and invasion in vitro as well as inhibited tumor growth in human melanoma xenograft mouse model in vivo.
Project description:In response to external or endogenous insults, eukaryotic cells can activate a common adaptive pathway called the integrated stress response (ISR). The ISR reduces global protein translation but upregulates the expression of stress response proteins to either restore cellular homeostasis or, in case of severe or prolonged stress, promote cell death. The bZIP transcription factor ATF4 plays a deciding role in cellular fate upon ISR activation, but the precise mechanisms underlying such decision-making remain unclear. Although bacterial infection has previously been observed to induce the ISR, the effects of this pathway on bacterial pathogenesis and host defense are not well understood. The functions of ATF4 in this process remain even more elusive. Using the Caenorhabditis elegans model to explore the bacterial infection-induced ISR, we found that infection with Salmonella enterica induced the GCN-2/eIF-2α/ATF-4 signaling pathway to modulate host defense against the infection. More specifically, ATF-4 suppressed the expression of ribosomal proteins in response to S. enterica exposure, reducing worm survival against the pathogen. Because ribosomal proteins are directly involved in protein translation, our data revealed an important, novel mechanism by which ATF-4 mediates the reduction of global translation under stress by inhibiting the expression of ribosomal proteins. ATF-4 also inhibited mitochondrial electron transport in response to S. enterica infection, likely functioning to dampen infection-induced production of reactive oxygen species. Moreover, our transcriptomic analysis showed that ATF-4 regulated the expression of collagens, a group of proteins that are tightly linked to stress resistance and longevity. Overall, we have identified specific molecular mechanisms by which ATF-4 determines cell fate upon ISR activation, providing a mechanistic understanding of how the bacterial infection-induced ISR impacts host physiology.
Project description:ChIP-seq of ATF-7::GFP from Wild Type or pmk-1 mutant animals exposed to either non-pathogenic E. coli OP50 or pathogenic P. aeruginosa PA14
Project description:The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows for rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and healthspan in C. elegans, independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, and specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo, via reduction of translation and ATF-4.
