bims-stacyt 2023-07-09 papers

J Biol Chem. 2023 Jun 29. pii: S0021-9258(23)02019-7. [Epub ahead of print] 104991

REDD1-dependent GSK3β dephosphorylation promotes NF-κB activation and macrophage infiltration in the retina of diabetic mice.

Siddharth Sunilkumar, Ashley M VanCleave, Christopher M McCurry, Allyson L Toro, Shaunaci A Stevens, Scot R Kimball, Michael D Dennis.

Increasing evidence supports a role for inflammation in the early development and progression of retinal complications caused by diabetes. We recently demonstrated that the stress response protein regulated in development and DNA damage response 1 (REDD1) promotes diabetes-induced retinal inflammation by sustaining canonical activation of nuclear transcription factor κB (NF-κB). The studies here were designed to identify signaling events whereby REDD1 promotes NF-κB activation in the retina of diabetic mice. We observed increased REDD1 expression in the retina of mice after 16-weeks of streptozotocin (STZ)-induced diabetes and found that REDD1 was essential for diabetes to suppress inhibitory phosphorylation of GSK3β at S9. In human retinal MIO-M1 Müller cell cultures, REDD1 deletion prevented dephosphorylation of GSK3β and increased NF-κB activation in response to hyperglycemic conditions. Expression of a constitutively active GSK3β variant restored NF-κB activation in cells deficient for REDD1. In cells exposed to hyperglycemic conditions, GSK3β knockdown inhibited NF-κB activation and pro-inflammatory cytokine expression by preventing inhibitor of κB (IκB) kinase (IKK) complex autophosphorylation and IκB degradation. In both the retina of STZ-diabetic mice and in Müller cells exposed to hyperglycemic conditions, GSK3 inhibition reduced NF-κB activity and prevented an increase in pro-inflammatory cytokine expression. In contrast with STZ-diabetic mice receiving a vehicle control, macrophage infiltration was not observed in the retina of STZ-diabetic mice treated with GSK3 inhibitor. Collectively, the findings support a model wherein diabetes enhances REDD1-dependent activation of GSK3β to promote canonical NF-κB signaling and the development of retinal inflammation.

Keywords: DDIT4; Diabetic Retinopathy; RTP801; inflammation

DOI: https://doi.org/10.1016/j.jbc.2023.104991

Cell Rep. 2023 Jul 04. pii: S2211-1247(23)00735-0. [Epub ahead of print]42(7): 112724

The integrated stress response effector ATF4 is an obligatory metabolic activator of NRF2.

Julia Katharina Charlotte Kreß, Christina Jessen, Anita Hufnagel, Werner Schmitz, Thamara Nishida Xavier da Silva, Ancély Ferreira Dos Santos, Laura Mosteo, Colin R Goding, José Pedro Friedmann Angeli, Svenja Meierjohann.

The redox regulator NRF2 becomes activated upon oxidative and electrophilic stress and orchestrates a response program associated with redox regulation, metabolism, tumor therapy resistance, and immune suppression. Here, we describe an unrecognized link between the integrated stress response (ISR) and NRF2 mediated by the ISR effector ATF4. The ISR is commonly activated after starvation or ER stress and plays a central role in tissue homeostasis and cancer plasticity. ATF4 increases NRF2 transcription and induces the glutathione-degrading enzyme CHAC1, which we now show to be critically important for maintaining NRF2 activation. In-depth analyses reveal that NRF2 supports ATF4-induced cells by increasing cystine uptake via the glutamate-cystine antiporter xCT. In addition, NRF2 upregulates genes mediating thioredoxin usage and regeneration, thus balancing the glutathione decrease. In conclusion, we demonstrate that the NRF2 response serves as second layer of the ISR, an observation highly relevant for the understanding of cellular resilience in health and disease.

Keywords: ATF4; CHAC1; CP: Cell biology; GSH; NRF2; SLC7A11; integrated stress response; melanoma

DOI: https://doi.org/10.1016/j.celrep.2023.112724

BMB Rep. 2023 Jul 04. pii: 5877. [Epub ahead of print]

Regulation of glucose and glutamine metabolism to overcome cisplatin resistance in intrahepatic cholangiocarcinoma.

So Mi Yang, Jueun Kim, Ji-Yeon Lee, Jung-Shin Lee, Ji Min Lee.

Intrahepatic cholangiocarcinoma (ICC) is one of the bile duct cancers and a rare malignant tumor with a poor prognosis owing to a lack of early diagnosis and resistance to conventional chemotherapy. A combination of gemcitabine and cisplatin is a treatment approach typically being attempted for the first line. However, its underlying mechanism of resistance to chemotherapy is poorly understood. We addressed this by studying the dynamics in the human ICC SCK cell line. Here, we report that the regulation of glucose and glutamine metabolism is a key factor in overcoming cisplatin resistance of SCK. Through RNA sequencing analysis, we discovered that the cell cycle-related gene set exhibits a high enrichment score in cisplatin-resistant SCK (SCK-R) cells rather than parental SCK (SCK WT) cells. Cell cycle progression correlates with increased nutrient requirement and cancer proliferation or metastasis. Commonly, cancer cells are dependent upon glucose and glutamine availability for survival and proliferation. Indeed, we observed increased expression of GLUT (glucose transporter), ASCT2 (glutamine transporter), and cancer progression markers in SCK-R cells. Thus, we inhibited enhanced metabolic reprogramming in SCK-R cells through nutrient starvation. Especially under glucose starvation, SCK-R cells are sensitized to cisplatin. Moreover, glutaminase-1 (GLS1), which is a mitochondrial enzyme involved in tumorigenesis and progression in cancer cells was upregulated in SCK-R cells. Targeting GLS1 with the GLS1 inhibitor CB-839 (telaglenastat) effectively reduced the expression of cancer progression markers. Taken together, our study suggests that a combination of GLUT inhibition, which mimics glucose starvation, and GLS1 inhibition could be a therapeutic strategy to increase the chemosensitivity of ICC.

Nat Cell Biol. 2023 Jul 03.

Prolonged hypoxia alleviates prolyl hydroxylation-mediated suppression of RIPK1 to promote necroptosis and inflammation.

The prolyl hydroxylation of hypoxia-inducible factor 1α (HIF-1α) mediated by the EGLN-pVHL pathway represents a classic signalling mechanism that mediates cellular adaptation under hypoxia. Here we identify RIPK1, a known regulator of cell death mediated by tumour necrosis factor receptor 1 (TNFR1), as a target of EGLN1-pVHL. Prolyl hydroxylation of RIPK1 mediated by EGLN1 promotes the binding of RIPK1 with pVHL to suppress its activation under normoxic conditions. Prolonged hypoxia promotes the activation of RIPK1 kinase by modulating its proline hydroxylation, independent of the TNFα-TNFR1 pathway. As such, inhibiting proline hydroxylation of RIPK1 promotes RIPK1 activation to trigger cell death and inflammation. Hepatocyte-specific Vhl deficiency promoted RIPK1-dependent apoptosis to mediate liver pathology. Our findings illustrate a key role of the EGLN-pVHL pathway in suppressing RIPK1 activation under normoxic conditions to promote cell survival and a model by which hypoxia promotes RIPK1 activation through modulating its proline hydroxylation to mediate cell death and inflammation in human diseases, independent of TNFR1.

DOI: https://doi.org/10.1038/s41556-023-01170-4

Trends Endocrinol Metab. 2023 Jun 30. pii: S1043-2760(23)00113-3. [Epub ahead of print]

Extracellular vesicle-mediated interorgan communication in metabolic diseases.

Sheng Hu, Yong Hu, Wei Yan.

The body partially maintains metabolic homeostasis through interorgan communication between metabolic organs under physiological conditions. This crosstalk is known to be mediated by hormones or metabolites, and has recently been expanding to include extracellular vesicles (EVs). EVs participate in interorgan communication under physiological and pathological conditions by encapsulating various bioactive cargoes, including proteins, metabolites, and nucleic acids. In this review we summarize the latest findings about the metabolic regulation of EV biogenesis, secretion, and components, and highlight the biological role of EV cargoes in interorgan communication in cancer, obesity, diabetes, and cardiovascular disease. We also discuss the potential application of EVs as diagnostic markers, and corresponding therapeutic strategies by EV engineering for both early detection and treatment of metabolic disorders.

Keywords: EV engineering; diagnosis; exosomes; extracellular vesicles; microvesicles; tumor metastasis

DOI: https://doi.org/10.1016/j.tem.2023.06.002