The IRE1α-XBP1 Signaling Axis Promotes Glycolytic Reprogramming in Response to Inflammatory Stimuli

English, Bevin C.; Savage, Hannah P; Mahan, Scott P; Diaz-Ochoa, Vladimir E.; Young, Benjamin E.; Abuaita, Basel H.; Sule, Gautam; Knight, Jason S.; O’Riordan, Mary X.; Bäumler, Andreas J.; Tsolis, Renée M.

doi:10.1128/mbio.03068-22

Cited by 8 publications

(4 citation statements)

References 68 publications

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“…It has been proposed that glutamine concentration stimulates q Gln rate and q NH4 [ 53 ], which is valid for the TAFE.X1, which expresses lower levels of h-XBP1s and at higher [Gln] also increases q Gln . Likewise, it has also been demonstrated that upregulation and induction of XBP1s downregulated the abundance of glutamine carriers (SNAT1, SNAT2, and ASCT2), limiting the glutamine influx in T-cells [ 22 , 54 ], via degradation of the carriers via ERAD [ 24 ]. This phenomenon was observed in our higher h-XBP1s overexpressor clone (TAFE.X2), which maintained basal q Gln regardless [Gln].…”

Section: Discussionmentioning

confidence: 99%

Enhancing Antibody-Specific Productivity: Unraveling the Impact of XBP1s Overexpression and Glutamine Availability in SP2/0 Cells

González-Pereira,

Trinh,

Vasuthasawat

et al. 2024

Bioengineering

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Augmentation of glycoprotein synthesis requirements induces endoplasmic reticulum (ER) stress, activating the unfolded protein response (UPR) and triggering unconventional XBP1 splicing. As a result, XBP1s orchestrates the expression of essential genes to reduce stress and restore homeostasis. When this mechanism fails, chronic stress may lead to apoptosis, which is thought to be associated with exceeding a threshold in XBP1s levels. Glycoprotein assembly is also affected by glutamine (Gln) availability, limiting nucleotide sugars (NS), and preventing compliance with the increased demands. In contrast, increased Gln intake synthesizes ammonia as a by-product, potentially reaching toxic levels. IgA2m(1)-producer mouse myeloma cells (SP2/0) were used as the cellular mammalian model. We explored how IgA2m(1)-specific productivity (qIgA2m(1)) is affected by (i) overexpression of human XBP1s (h-XBP1s) levels and (ii) Gln availability, evaluating the kinetic behavior in batch cultures. The study revealed a two and a five-fold increase in qIgA2m(1) when lower and higher levels of XBP1s were expressed, respectively. High h-XBP1s overexpression mitigated not only ammonia but also lactate accumulation. Moreover, XBP1s overexpressor showed resilience to hydrodynamic stress in serum-free environments. These findings suggest a potential application of h-XBP1s overexpression as a feasible and cost-effective strategy for bioprocess scalability.

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Section: Discussionmentioning

confidence: 99%

Enhancing Antibody-Specific Productivity: Unraveling the Impact of XBP1s Overexpression and Glutamine Availability in SP2/0 Cells

González-Pereira,

Trinh,

Vasuthasawat

et al. 2024

Bioengineering

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“…Studies have shown that macrophages obtain energy through glycolysis during inflammatory activation and that the inhibition of glycolysis can inhibit inflammation [ 22 , 23 , 24 ]. Our study found that the ECAR increased, OCR decreased, and glycolysis increased during glucose metabolism when RAW264.7 cells were stimulated by LPS.…”

Section: Discussionmentioning

confidence: 99%

Terpinen-4-ol Improves Lipopolysaccharide-Induced Macrophage Inflammation by Regulating Glutamine Metabolism

Liu,

Tang,

Zhang

et al. 2024

Foods

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Terpinen-4-ol (T-4-O) is an important component of tea tree oil and has anti-inflammatory effects. Currently, there are very few studies on the mechanisms by which T-4-O improves lipopolysaccharide (LPS)-induced macrophage inflammation. In this study, LPS-stimulated mouse RAW264.7 macrophages were used as a model to analyze the effects of T-4-O on macrophage inflammatory factors and related metabolic pathways in an inflammatory environment. The results showed that T-4-O significantly decreased the expression levels of inflammatory cytokines induced by LPS. Cellular metabolism results showed that T-4-O significantly decreased the ratio of the extracellular acidification rate and oxygen consumption rate. Non-targeted metabolomics results showed that T-4-O mainly affected glutamine and glutamate metabolism and glycine, serine, and threonine metabolic pathways. qPCR results showed that T-4-O increased the transcript levels of GLS and GDH and promoted glutamine catabolism. Western blotting results showed that T-4-O inhibited the mTOR and IκB, thereby decreasing NF-κB activity. The overall results showed that T-4-O inhibited mTOR phosphorylation to promote glutamine metabolism and increased cell oxidative phosphorylation levels, thereby inhibiting the expression of LPS-induced inflammatory cytokines.

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“…IRE1α activity is crucial for the maturation and function of highly secretory cell types, such as plasma cells 77,78 , pancreatic beta cells 79 , macrophages 6,80 , and T cells 81 . Additionally, considering the broad roles of IRE1α and XBP1S in innate immunity, including cytokine induction 6,10 , metabolic plasticity 24 , ROS production, and microbicidal activity 12,13 , proactive strategies for IRE1α activation prior to protein misfolding may be important for innate immune regulation. Further elucidation of the mechanisms driving protein misfolding-independent IRE1α activation will identify targets for tuning of IRE1α activity, with potential for therapeutic utility for diseases in which aberrant IRE1α activity may contribute to disease progression, such as cancer and obesity 82,83 .…”

Section: Discussionmentioning

confidence: 99%

“…IRE1α has broad regulatory roles and consequences for infection and immunity. For example, the IRE1α-XBP1S axis can promote the expression of proinflammatory cytokines 6,22 , modulate metabolic plasticity 24 , and promote ER homeostasis 25 during infection. Additionally, IRE1α can facilitate intra-organelle communication for ER-mitochondria calcium signaling and promotion of reactive oxygen species (ROS) generation 12,13,26 .…”

Section: Introductionmentioning

confidence: 99%

Non-canonical activation of IRE1α duringCandida albicansinfection enhances macrophage fungicidal activity

McFadden,

Reynolds,

Michmerhuizen

et al. 2023

Preprint

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Infection by intracellular pathogens can trigger activation of the IRE1α branch of the unfolded protein response (UPR), which then modulates innate immunity and infection outcomes during bacterial or viral infection. However, the mechanisms by which infection activates IRE1α have not been fully elucidated. While recognition of microbe-associated molecular patterns can activate IRE1α, it is unclear whether this depends on the canonical role of IRE1α in detecting misfolded proteins. Here, we report thatCandida albicansinfection of macrophages results in IRE1α activation through C-type lectin receptor signaling, reinforcing a role for IRE1α as a central regulator of host responses to infection by a broad range of pathogens. However, IRE1α activation was not preceded by protein misfolding in response to eitherC. albicansinfection or lipopolysaccharide treatment, implicating a non-canonical mode of IRE1α activation after recognition of microbial patterns. Investigation of the phenotypic consequences of IRE1α activation in macrophage antimicrobial responses revealed that IRE1α activity enhances the fungicidal activity of macrophages. Macrophages lacking IRE1α activity displayed inefficient phagolysosomal fusion, enablingC. albicansto evade fungal killing and escape the phagosome. Together, these data provide mechanistic insight for the non-canonical activation of IRE1α during infection, and reveal central roles for IRE1α in macrophage antifungal responses.

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The IRE1α-XBP1 Signaling Axis Promotes Glycolytic Reprogramming in Response to Inflammatory Stimuli

Cited by 8 publications

References 68 publications

Enhancing Antibody-Specific Productivity: Unraveling the Impact of XBP1s Overexpression and Glutamine Availability in SP2/0 Cells

Enhancing Antibody-Specific Productivity: Unraveling the Impact of XBP1s Overexpression and Glutamine Availability in SP2/0 Cells

Terpinen-4-ol Improves Lipopolysaccharide-Induced Macrophage Inflammation by Regulating Glutamine Metabolism

Non-canonical activation of IRE1α duringCandida albicansinfection enhances macrophage fungicidal activity

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