Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals

Quirós, Pedro M.; Prado, Miguel A.; Zamboni, Nicola; D’Amico, Davide; Williams, Robert W.; Finley, Daniel; Gygi, Steven P.; Auwerx, Johan

doi:10.1083/jcb.201702058

Cited by 645 publications

(733 citation statements)

References 94 publications

Supporting

Mentioning

634

Contrasting

Order By: Relevance

“…Stress response functions of implicated metabolites are consistent with known stress roles of NAMPT (Amelio et al, 2014; Wang et al, 2011). Interestingly, PHGDH has also been shown to be induced as a metabolic stress response (DeNicola et al, 2015; Quirós et al, 2017), and our data suggest that these scenarios would require support by a sufficiently active NAD + salvage pathway. Although both NAMPT and PHGDH are regulated by the stress response (Cerna et al, 2012), the requirement for NAD + salvage in cells with genomically amplified PHGDH levels is particularly important, since PHGDH inhibitors are only beginning to emerge and their efficacy is yet unproven.…”

Section: Discussionmentioning

confidence: 58%

“…Pharmacological depletion of NAD + is being explored broadly as a cancer treatment, leading to the development of drugs such as FK866/APO866 and epacadostat, inhibitors of salvage and de novo NAD + biosynthesis, respectively (Hasmann and Schemainda, 2003; Hjarnaa et al, 1999). Recent work suggests that redox molecules such as NAD + support stress responses in cancer cells by regulating amino acid metabolism that, in turn, supplies precursors for detoxifying reactive oxygen species (ROS) (Quirós et al, 2017). Indeed, 3-phospho-glycerate dehydrogenase (PHGDH), the first enzyme of the mammalian serine biosynthesis pathway (SBP), is NAD + dependent.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

et al. 2018

Self Cite

View full text Add to dashboard Cite

NAD is a key metabolic redox cofactor that is regenerated from nicotinamide through the NAD salvage pathway. Here, we find that inhibiting the NAD salvage pathway depletes serine biosynthesis from glucose by impeding the NAD-dependent protein, 3-phosphoglycerate dehydrogenase (PHGDH). Importantly, we find that PHGDH breast cancer cell lines are exquisitely sensitive to inhibition of the NAD salvage pathway. Further, we find that PHGDH protein levels and those of the rate-limiting enzyme of NAD salvage, NAMPT, correlate in ER-negative, basal-like breast cancers. Although NAD salvage pathway inhibitors are actively being pursued in cancer treatment, their efficacy has been poor, and our findings suggest that they may be effective for PHGDH-dependent cancers.

show abstract

Section: Discussionmentioning

confidence: 58%

Section: Introductionmentioning

confidence: 99%

The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…In accordance with literature data, gene expression is considerably less affected by an ISR, than the proteome. 41 In sum, our experiments support the induction of mitochondrial stress by plecstatin-2, particularly an ISR, as an additional drug effect besides plectin-targeting.…”

mentioning

confidence: 51%

Time-dependent shotgun proteomics revealed distinct effects of an organoruthenium prodrug and its activation product on colon carcinoma cells

et al. 2019

View full text Add to dashboard Cite

Time-dependent shotgun proteomics revealed distinct effects of an organoruthenium prodrug and its activation product on colon carcinoma cellsThe unravelling of target interactions in cancer cells is a crucial process for identifying promising metal-based anticancer agents. Therefore, target profiles were analysed in a time-dependent manner using proteomics techniques by accounting for the hydrolysis kinetics of plecstatin, an organometallic ruthenium(arene) derivative. While the intact prodrug provoked a cytoprotective integrated stress response, which was further verified by gene expression studies, the activated species was responsible for the target engagement with plectin, the previously validated protein target. As featured in:ISSN 1756-591X Activation kinetics of metallo-prodrugs control the types of possible interactions with biomolecules. The intact metallo-prodrug is able to engage with potential targets by purely non-covalent bonding, while the activated metallodrug can form additional coordination bonds. It is hypothesized that the additional coordinative bonding might be favourable with respect to the target selectivity of activated metallodrugs. Thus, a time-dependent shotgun proteomics study was conducted in HCT116 colon carcinoma cells with plecstatins, which are organoruthenium anticancer drug candidates. First, the target selectivity was evaluated in a time-dependent fashion, which accounted for their hydrolysis kinetics. The binding selectivity increased from 50-to 160-fold and the average specificity from 0.72 to 0.86, respectively, from the 2 h to the 4 h target profiling experiment. Target profiling after 19 h did not reveal significant enrichments, possibly due to deactivation of the probe via arene cleavage. Up to 450 interactors were identified in the target profiling experiments. A plecstatin analogue that substituted a hydrogen bond acceptor with a hydrogen bond donor abrogated the target selectivity for plectin in HCT116 whole cell lysates, underlining the necessity of this hydrogen bond acceptor for a strong interaction between plecstatin and plectin. Second, time-dependent response profiling experiments provided evidence that plecstatin-2 induced an integrated stress response (ISR) in HCT116 cell culture. The phosphorylation of eIF2a, a key mediator of the ISR, after 3 h treatment indicated that this perturbation was initiated by the intact plecstatin-2 prodrug, while the effects of plectin-targeting are mediated by activated plecstatin-2. Significance to metallomicsCell-level investigations of metallodrugs by shotgun proteomics are still scarce despite the evident advantages of these methods. We performed time-dependent target profiling experiments with organoruthenium-based plecstatins in cell lysates of HCT116 colon carcinoma cells. The changes in target selectivity over time correlated with the activation status of the metallo-prodrug. The target engagement of the plecstatins was tested by substituting a hydrogen bond acceptor with a hydrogen bond donor, which abrogated the plect...

show abstract

“…Because the modification level of this site appears to be the highest among the m 1 A sites in mt-mRNAs (Table S3), we also surveyed publicly available RNA-seq data for the presence of m 1 A at this position (Kondo et al, 2017; Li et al, 2016a; Li et al, 2015; Quiros et al, 2017). Although the RT conditions differ greatly among the datasets, we were able to consistently find a mutation rate of ~2–9% for this position (Figure 4E).…”

Section: Resultsmentioning

confidence: 99%

Base-Resolution Mapping Reveals Distinct m1A Methylome in Nuclear- and Mitochondrial-Encoded Transcripts

et al. 2017

View full text Add to dashboard Cite

SUMMARY Gene expression can be post-transcriptionally regulated via dynamic and reversible RNA modifications. N1-methyladenosine (m1A) is a recently identified mRNA modification; however, little is known about its precise location and biogenesis. Here, we develop a base-resolution m1A profiling method, based on m1A-induced misincorporation during reverse transcription, and report distinct classes of m1A methylome in the human transcriptome. m1A in 5′-UTR, particularly those at the mRNA cap, associate with increased translation efficiency. A different, small subset of m1A exhibit a GUUCRA tRNA-like motif, are evenly distributed in the transcriptome and are dependent on the methyltransferase TRMT6/61A. Additionally, we show that m1A is prevalent in the mitochondrial-encoded transcripts. Manipulation of m1A level via TRMT61B, a mitochondria-localizing m1A methyltransferase, demonstrates that m1A in mitochondrial mRNA interferes with translation. Collectively, our approaches reveal distinct classes of m1A methylome and provide a resource for functional studies of m1A-mediated epitranscriptomic regulation.

show abstract

Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals

Cited by 645 publications

References 94 publications

The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

The NAD+ Salvage Pathway Supports PHGDH-Driven Serine Biosynthesis

Time-dependent shotgun proteomics revealed distinct effects of an organoruthenium prodrug and its activation product on colon carcinoma cells

Base-Resolution Mapping Reveals Distinct m1A Methylome in Nuclear- and Mitochondrial-Encoded Transcripts

Contact Info

Product

Resources

About