A multi-omics analysis reveals the unfolded protein response regulon and stress-induced resistance to folate-based antimetabolites.

Nature Communications
Stefan ReichJan Medenbach

Abstract

Stress response pathways are critical for cellular homeostasis, promoting survival through adaptive changes in gene expression and metabolism. They play key roles in numerous diseases and are implicated in cancer progression and chemoresistance. However, the underlying mechanisms are only poorly understood. We have employed a multi-omics approach to monitor changes to gene expression after induction of a stress response pathway, the unfolded protein response (UPR), probing in parallel the transcriptome, the proteome, and changes to translation. Stringent filtering reveals the induction of 267 genes, many of which have not previously been implicated in stress response pathways. We experimentally demonstrate that UPR-mediated translational control induces the expression of enzymes involved in a pathway that diverts intermediate metabolites from glycolysis to fuel mitochondrial one-carbon metabolism. Concomitantly, the cells become resistant to the folate-based antimetabolites Methotrexate and Pemetrexed, establishing a direct link between UPR-driven changes to gene expression and resistance to pharmacological treatment.

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Citations

Sep 30, 2020·Proceedings of the National Academy of Sciences of the United States of America·Jiajun HanHui Peng
Apr 17, 2021·ACS Pharmacology & Translational Science·Christine R CuthbertsonNouri Neamati
Oct 11, 2020·Trends in Cell Biology·Matías González-QuirozRémy Pedeux
May 1, 2021·International Journal of Molecular Sciences·Rebeka PopovicL Miguel Martins
Jul 7, 2021·Cellular and Molecular Life Sciences : CMLS·Eva-Maria EcklLucas T Jae
Aug 3, 2021·Ageing Research Reviews·Md Sahab UddinLee Wei Lim
Dec 1, 2021·The New Phytologist·Hui CaoA Harvey Millar
Jan 16, 2022·Biochimica Et Biophysica Acta. Molecular Cell Research·Priyanka MallickSaikat Chakrabarti

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Methods Mentioned

BETA
glycosylation
chemical treatments
transfection
PCR
electrophoresis
RNA Assay
RNA-seq
Illumina sequencing
Protein Assay
Assay

Key Resources (RRID) Mentioned

CVCL_U427
CVCL_0394
AB_2119845
AB_10679929
AB_315907
AB_2616025
AB_10692650
AB_732117
AB_477593
AB_476693

Software Mentioned

Progenesis QI for Proteomics
Tandem
gridExtra
reshape2
RiboDiff
trimmomatic
GeneOntology
PeptideShaker
STAR
DAVID

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