Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways

Popovic, Rebeka; Celardo, Ivana; Yu, Yizhou; Costa, Ana C.; Loh, Samantha H. Y.; Martins, L. Miguel

doi:10.3390/ijms22094598

Open AccessArticle

Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways

by

Rebeka Popovic

,

Ivana Celardo

,

Yizhou Yu

,

Ana C. Costa

,

Samantha H. Y. Loh

and

L. Miguel Martins

^*

MRC Toxicology Unit, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge CB2 1QR, UK

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2021, 22(9), 4598; https://doi.org/10.3390/ijms22094598

Submission received: 13 March 2021 / Revised: 19 April 2021 / Accepted: 23 April 2021 / Published: 27 April 2021

(This article belongs to the Special Issue Physiological and Pathological Aspects of Unfolded Protein Response)

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Abstract

In Drosophila, endoplasmic reticulum (ER) stress activates the protein kinase R-like endoplasmic reticulum kinase (dPerk). dPerk can also be activated by defective mitochondria in fly models of Parkinson’s disease caused by mutations in pink1 or parkin. The Perk branch of the unfolded protein response (UPR) has emerged as a major toxic process in neurodegenerative disorders causing a chronic reduction in vital proteins and neuronal death. In this study, we combined microarray analysis and quantitative proteomics analysis in adult flies overexpressing dPerk to investigate the relationship between the transcriptional and translational response to dPerk activation. We identified tribbles and Heat shock protein 22 as two novel Drosophila activating transcription factor 4 (dAtf4) regulated transcripts. Using a combined bioinformatics tool kit, we demonstrated that the activation of dPerk leads to translational repression of mitochondrial proteins associated with glutathione and nucleotide metabolism, calcium signalling and iron-sulphur cluster biosynthesis. Further efforts to enhance these translationally repressed dPerk targets might offer protection against Perk toxicity.

Keywords: Drosophila; Drosophila protein kinase RNA (PKR)-like ER kinase (dPerk); ER stress; unfolded protein response; activating transcription factor 4 (ATF4)

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MDPI and ACS Style

Popovic, R.; Celardo, I.; Yu, Y.; Costa, A.C.; Loh, S.H.Y.; Martins, L.M. Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways. Int. J. Mol. Sci. 2021, 22, 4598. https://doi.org/10.3390/ijms22094598

AMA Style

Popovic R, Celardo I, Yu Y, Costa AC, Loh SHY, Martins LM. Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways. International Journal of Molecular Sciences. 2021; 22(9):4598. https://doi.org/10.3390/ijms22094598

Chicago/Turabian Style

Popovic, Rebeka, Ivana Celardo, Yizhou Yu, Ana C. Costa, Samantha H. Y. Loh, and L. Miguel Martins. 2021. "Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways" International Journal of Molecular Sciences 22, no. 9: 4598. https://doi.org/10.3390/ijms22094598

APA Style

Popovic, R., Celardo, I., Yu, Y., Costa, A. C., Loh, S. H. Y., & Martins, L. M. (2021). Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways. International Journal of Molecular Sciences, 22(9), 4598. https://doi.org/10.3390/ijms22094598

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Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways

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