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

Almanza, Aitor; Mnich, Katarzyna; Blomme, Arnaud; Robinson, Claire M.; Blanco, Giovanny Rodriguez; Kierszniowska, Sylwia; McGrath, Eoghan P.; Gallo, Matthieu Le; Pilalis, Eleftherios; Swinnen, Johannes V.; Chatziioannou, Aristotelis; Chevet, Éric; Gorman, Adrienne M.; Samali, Afshin

doi:10.1038/s41467-022-30159-0

Cited by 41 publications

(30 citation statements)

References 57 publications

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“…In addition to splicing the XBP1 transcript, activated IRE1α also degrades specific RNA species in a process called regulated IRE1α-dependent decay, or RIDD. Intriguingly, RIDD, which contributes to the intracellular survival of Brucella (28), influences the metabolism of cancer cells (52) and thus may also be affecting the metabolism of CAM.…”

Section: Discussionmentioning

confidence: 99%

The IRE1α-XBP1 signaling axis promotes glycolytic reprogramming in response to inflammatory stimuli

English¹,

Savage²,

Mahan³

et al. 2022

Preprint

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Immune cells must be able to adjust their metabolic programs to effectively carry out their effector functions. Here, we show that the ER stress sensor IRE1α and its downstream transcription factor XBP1 enhance the upregulation of glycolysis in classically activated macrophages (CAM). The IRE1α-XBP1 signaling axis supports this glycolytic switch in macrophages when activated by LPS stimulation or infection with the intracellular bacterial pathogenBrucella abortus. Importantly, these different inflammatory stimuli have distinct mechanisms of IRE1α activation; while TLR4 supports glycolysis under both conditions, TLR4 is required for activation of IRE1α in response to LPS treatment but notB. abortusinfection. Though IRE1α and XBP1 are necessary for maximal induction of glycolysis in CAM, activation of this pathway is not sufficient to increase the glycolytic rate of macrophages, indicating that the cellular context in which this pathway is activated ultimately dictates the cell’s metabolic response and that IRE1α activation may be a way to fine-tune metabolic reprogramming.IMPORTANCEThe immune system must be able to tailor its response to different types of pathogens in order to eliminate them and protect the host. When confronted with bacterial pathogens, macrophages, frontline defenders in the immune system, switch to a glycolysis-driven metabolism to carry out their antibacterial functions. Here, we show that IRE1α, a sensor of ER stress, and its downstream transcription factor XBP1 support glycolysis in macrophages during infection withBrucella abortusor challenge withSalmonellaLPS. Interestingly, these stimuli activate IRE1α by independent mechanisms. While the IRE1α-XBP1 signaling axis promotes the glycolytic switch, activation of this pathway is not sufficient to increase glycolysis in macrophages. This study furthers our understanding of the pathways that drive macrophage immunometabolism and highlights a new role for IRE1α and XBP1 in innate immunity.

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Section: Discussionmentioning

confidence: 99%

The IRE1α-XBP1 signaling axis promotes glycolytic reprogramming in response to inflammatory stimuli

English¹,

Savage²,

Mahan³

et al. 2022

Preprint

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“…To investigate the potential mechanisms determining the reduction of CPT2 expression in the kidney, we focused on endoplasmic reticulum (ER) stress, which is known to be activated in the acute kidney injury response (36)(37)(38), and drives tissue remodeling associated with CKD (39)(40)(41). Moreover, ER stress profoundly reshapes the cell lipidome (42). Supporting a role of ER stress in regulating CPT2 expression in the kidney in the course of CKD, we observed in the cohort of 201 CKD patients and healthy donors cited above (31) that ER stress response genes (PDI, HSPA5 and XBP1) (43), and biomarkers of ER stress-related kidney diseases (LNC2, and MANF) (39,44) were highly expressed in the tubulointerstitial compartment of patients with low eGFR, and, importantly, CPT2 expression was reduced in kidneys expressing the ER stress signature (Figure 6A).…”

Section: Endoplasmic Reticulum Stress Represses Cpt2 Expressionmentioning

confidence: 99%

Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury

Rinaldi¹,

Lazareth²,

Poindessous³

et al. 2022

JCI Insight

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Energy metabolism failure in proximal tubule cells (PTC) is a hallmark of chronic kidney injury.We combined transcriptomic, metabolomic and lipidomic approaches in experimental models and patient cohorts to investigate the molecular bases of the progression to chronic kidney allograft injury initiated by ischemia-reperfusion injury (IRI). The urinary metabolome of kidney transplant recipients with chronic allograft injury and who experienced severe IRI was significantly enriched with long chain fatty acids (FA). We identified a renal FA-related gene signature with low levels of Cpt2 and Acsm5 and high levels of Acsl4 and Acsm5 associated with IRI, transition to chronic injury, and established CKD in mouse models and kidney transplant recipients. The findings were consistent with the presence of Cpt2 -, Acsl4 + , Acsl5 + , Acsm5 -PTC failing to recover from IRI as identified by snRNAseq. In vitro experiments indicated that endoplasmic reticulum (ER) stress contributes to CPT2 repression, which, in turn, promotes lipids accumulation, drives profibrogenic epithelial phenotypic changes, and activates the unfolded protein response. ER stress through CPT2 inhibition and lipid accumulation, engages an auto-amplification loop leading to lipotoxicity and self-sustained cellular stress. Thus, IRI imprints a persistent FA metabolism disturbance in the proximal tubule sustaining the progression to chronic kidney allograft injury.

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“…IRE1α is a bifunctional enzyme that senses the accumulation of unfolded proteins, leading to its dimerization and autophosphorylation ( 9 , 75 , 76 ). Subsequently, IRE1α cleaves mRNA encoding the UPR-specific transcription factor, X-box binding protein 1 (XBP1) resulting in its active form spliced XBP1 (XBP1s) ( 9 ).…”

Section: Regulation Of the Unfolded Protein Responsementioning

confidence: 99%

Tidy up - The unfolded protein response in sepsis

Vivas

Weis²

2022

Front. Immunol.

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Pathogens, their toxic byproducts, and the subsequent immune reaction exert different forms of stress and damage to the tissue of the infected host. This stress can trigger specific transcriptional and post-transcriptional programs that have evolved to limit the pathogenesis of infectious diseases by conferring tissue damage control. If these programs fail, infectious diseases can take a severe course including organ dysfunction and damage, a phenomenon that is known as sepsis and which is associated with high mortality. One of the key adaptive mechanisms to counter infection-associated stress is the unfolded protein response (UPR), aiming to reduce endoplasmic reticulum stress and restore protein homeostasis. This is mediated via a set of diverse and complementary mechanisms, i.e. the reduction of protein translation, increase of protein folding capacity, and increase of polyubiquitination of misfolded proteins and subsequent proteasomal degradation. However, UPR is not exclusively beneficial since its enhanced or prolonged activation might lead to detrimental effects such as cell death. Thus, fine-tuning and time-restricted regulation of the UPR should diminish disease severity of infectious disease and improve the outcome of sepsis while not bearing long-term consequences. In this review, we describe the current knowledge of the UPR, its role in infectious diseases, regulation mechanisms, and further clinical implications in sepsis.

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

Cited by 41 publications

References 57 publications

The IRE1α-XBP1 signaling axis promotes glycolytic reprogramming in response to inflammatory stimuli

The IRE1α-XBP1 signaling axis promotes glycolytic reprogramming in response to inflammatory stimuli

Impaired fatty acid metabolism perpetuates lipotoxicity along the transition to chronic kidney injury

Tidy up - The unfolded protein response in sepsis

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