Translational Activation of ATF4 through Mitochondrial Anaplerotic Metabolic Pathways Is Required for DLBCL Growth and Survival

Abstract

Diffuse large B-cell lymphomas (DLBCL) are broadly dependent on anaplerotic metabolism regulated by mitochondrial SIRT3. Herein we find that translational upregulation of ATF4 is coupled with anaplerotic metabolism in DLBCLs due to nutrient deprivation caused by SIRT3 driving rapid flux of glutamine into the tricarboxylic acid (TCA) cycle. SIRT3 depletion led to ATF4 downregulation and cell death, which was rescued by ectopic ATF4 expression. Mechanistically, ATF4 translation is inhibited in SIRT3-deficient cells due to the increased pools of amino acids derived from compensatory autophagy and decreased glutamine consumption by the TCA cycle. Absence of ATF4 further aggravates this state through downregulation of its target genes, including genes for amino acid biosynthesis and import. Collectively, we identify a SIRT3–ATF4 axis required to maintain survival of DLBCL cells by enabling them to optimize amino acid uptake and utilization. Targeting ATF4 translation can potentiate the cytotoxic effect of SIRT3 inhibitor to DLBCL cells. Significance: We discovered the link between SIRT3 and ATF4 in DLBCL cells, which connected lymphoma amino acid metabolism with ATF4 translation via metabolic stress signals. SIRT3–ATF4 axis is required in DLBCL cells regardless of subtype, which indicates a common metabolic vulnerability in DLBCLs and can serve as a therapeutic target. This article is highlighted in the In This Issue feature, p. 1

Transcriptional and metabolic remodeling in clear cell renal cell carcinoma caused by ATF4 activation and the integrated stress response (ISR)

“…Rapidly growing tumors face nutrient deprivation and/or hypoxia, and activation of the ISR dampens cellular stress, enabling tumors to proliferate despite nutrient/hypoxia limitations 17–20 . Although ATF4 protein levels generally are reported to be controlled translationally via phosphorylation of eukaryotic initiation factor2 (EIF2α [EIF2S1]) under stress conditions, 21 in B‐cell lymphomas SIRT3 can drive ATF4 protein expression via translational regulation that does not involve EIF2α phosphorylation 22 . ATF4 can also be activated by mTORC1 by a mechanism independent of EIF2α phosphorylation 23,24 .…”

“…[17][18][19][20] Although ATF4 protein levels generally are reported to be controlled translationally via phosphorylation of eukaryotic initiation factor2 (EIF2α [EIF2S1]) under stress conditions, 21 in B-cell lymphomas SIRT3 can drive ATF4 protein expression via translational regulation that does not involve EIF2α phosphorylation. 22 ATF4 can also be activated by mTORC1 by a mechanism independent of EIF2α phosphorylation. 23,24 ATF4 and its target genes can promote angiogenesis and metastasis.…”

Targeting aggressive B-cell lymphomas through pharmacological activation of the mitochondrial protease OMA1

“…Common to all tumors is the need to balance the demands of rapid proliferation with nutrient availability and accumulation of metabolic end products in the tumor microenvironment( 1 ). Mitochondria play a key role in altered cancer cell metabolism, cellular stress and survival pathways and are increasingly being considered as targets in cancer( 2–4 ). Several Mitochondria Quality Control (MQC) pathways serve to maintain the integrity of mitochondria.…”

“…MQC pathways signal to cytosolic pathways that control the ATF4-Integrated Stress Response (ISR), an adaptive gene expression program controlling amino acid biosynthesis and transport, redox homeostasis and enhanced protein folding (5,8,9). The ATF4-ISR facilitates adaptation to the tumor microenvironment and is shown to be a pharmacologically targetable tumor dependency (2,10). Activation of the ISR is initiated by phosphorylation of the translation initiation factor eIF2, which leads to a decrease in protein synthesis and increased activity of the nuclear transcription factors ATF3, ATF4, ATF5 and DDIT3 (11)(12)(13)(14).…”

“…Mitochondria play a key role in altered cancer cell metabolism, cellular stress and survival pathways and are increasingly being considered as targets in cancer (2)(3)(4). Several Mitochondria Quality Control (MQC) pathways serve to maintain the integrity of mitochondria.…”