Regulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer

Aitor Almanza, Katarzyna Mnich, Arnaud Blomme, Claire M. Robinson, Giovanny Rodriguez-Blanco, Sylwia Kierszniowska, Eoghan P. McGrath, Matthieu Gallo, Eleftherios Pilalis, Johannes V. Swinnen, Aristotelis Chatziioannou, Eric Chevet, Adrienne M. Gorman and Afshin Samali ()
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Aitor Almanza: National University of Ireland
Katarzyna Mnich: National University of Ireland
Arnaud Blomme: CRUK Beatson Institute
Claire M. Robinson: National University of Ireland
Giovanny Rodriguez-Blanco: CRUK Beatson Institute
Sylwia Kierszniowska: metaSysX GmbH
Eoghan P. McGrath: National University of Ireland
Matthieu Gallo: University of Rennes
Eleftherios Pilalis: e-NIOS Applications PC
Johannes V. Swinnen: KU Leuven Cancer Institute
Aristotelis Chatziioannou: e-NIOS Applications PC
Eric Chevet: University of Rennes
Adrienne M. Gorman: National University of Ireland
Afshin Samali: National University of Ireland

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract IRE1α is constitutively active in several cancers and can contribute to cancer progression. Activated IRE1α cleaves XBP1 mRNA, a key step in production of the transcription factor XBP1s. In addition, IRE1α cleaves select mRNAs through regulated IRE1α-dependent decay (RIDD). Accumulating evidence implicates IRE1α in the regulation of lipid metabolism. However, the roles of XBP1s and RIDD in this process remain ill-defined. In this study, transcriptome and lipidome profiling of triple negative breast cancer cells subjected to pharmacological inhibition of IRE1α reveals changes in lipid metabolism genes associated with accumulation of triacylglycerols (TAGs). We identify DGAT2 mRNA, encoding the rate-limiting enzyme in TAG biosynthesis, as a RIDD target. Inhibition of IRE1α, leads to DGAT2-dependent accumulation of TAGs in lipid droplets and sensitizes cells to nutritional stress, which is rescued by treatment with the DGAT2 inhibitor PF-06424439. Our results highlight the importance of IRE1α RIDD activity in reprograming cellular lipid metabolism.

Date: 2022
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DOI: 10.1038/s41467-022-30159-0

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