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

IRE1 alpha cleaves several mRNAs upon accumulation of misfolded proteins. Here the authors show that active IRE1 alpha cleaves DGAT2 mRNA encoding the rate-limiting enzyme in the synthesis of triacylglycerols, suggesting a role of IRE1 alpha in reprogramming lipid metabolism in cancer cells. IRE1 alpha is constitutively active in several cancers and can contribute to cancer progression. Activated IRE1 alpha cleaves XBP1 mRNA, a key step in production of the transcription factor XBP1s. In addition, IRE1 alpha cleaves select mRNAs through regulated IRE1 alpha-dependent decay (RIDD). Accumulating evidence implicates IRE1 alpha 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 IRE1 alpha 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 IRE1 alpha, 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 IRE1 alpha RIDD activity in reprograming cellular lipid metabolism.