bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–10–20
23 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.
  2. Quantification of nutrient fluxes during acute exercise in mice.
  3. Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.
  4. Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling.
  5. Itaconate modulates mitochondria for antiviral IFN-β.
  6. Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation.
  7. Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
  8. PD-L1 protects tumor-associated dendritic cells from ferroptosis during immunogenic chemotherapy.
  9. Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice.
  10. Selective utilization of glucose metabolism guides mammalian gastrulation.
  11. A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice.
  12. Methionine-SAM metabolism-dependent ubiquinone synthesis is crucial for ROS accumulation in ferroptosis induction.
  13. Generation and characterization of a conditional eNOS knock out mouse model for cell-specific reactivation of eNOS in gain-of-function studies.
  14. Macropinocytosis mediates resistance to loss of glutamine transport in triple-negative breast cancer.
  15. Thermal proteome profiling reveals fructose-1,6-bisphosphate as a phosphate donor to activate phosphoglycerate mutase 1.
  16. Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency.
  17. Phosphatidylserine phospholipase A1 enables GPR34-dependent immune cell accumulation in the peritoneal cavity.
  18. The acid-sensing receptor GPR65 on tumor macrophages drives tumor growth in obesity.
  19. A sphingolipid rheostat controls apoptosis versus apical cell extrusion as alternative tumour-suppressive mechanisms.
  20. Oncogenic accumulation of cysteine promotes cancer cell proliferation by regulating the translation of D-type cyclins.
  21. A TBK1-independent primordial function of STING in lysosomal biogenesis.
  22. Palmitoleate protects against Lipopolysaccharide-induced Inflammation and Inflammasome Activity.
  23. Visualizing the spatial organization of monocytes, interstitial macrophages, and tissue-specific macrophages in situ.
  1. Nat Metab. 2024 Oct 14.
    Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.
    Ekaterina D Korobkina, Camila Martinez Calejman, John A Haley, Miranda E Kelly, Huawei Li, Maria Gaughan, Qingbo Chen, Hannah L Pepper, Hafsah Ahmad, Alexander Boucher, Shelagh M Fluharty, Te-Yueh Lin, Anoushka Lotun, Jessica Peura, Sophie Trefely, Courtney R Green, Paula Vo, Clay F Semenkovich, Jason R Pitarresi, Jessica B Spinelli, Ozkan Aydemir, Christian M Metallo, Matthew D Lynes, Cholsoon Jang, Nathaniel W Snyder, Kathryn E Wellen, David A Guertin.
      Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT.
    DOI:  https://doi.org/10.1038/s42255-024-01143-3
  2. Cell Metab. 2024 Oct 11. pii: S1550-4131(24)00374-7. [Epub ahead of print]
    Quantification of nutrient fluxes during acute exercise in mice.
    Jessie Axsom, Tara TeSlaa, Won Dong Lee, Qingwei Chu, Alexis Cowan, Marc R Bornstein, Michael D Neinast, Caroline R Bartman, Megan C Blair, Kristina Li, Chelsea Thorsheim, Joshua D Rabinowitz, Zoltan Arany.
      Despite the known metabolic benefits of exercise, an integrated metabolic understanding of exercise is lacking. Here, we use in vivo steady-state isotope-labeled infusions to quantify fuel flux and oxidation during exercise in fasted, fed, and exhausted female mice, revealing several novel findings. Exercise strongly promoted glucose fluxes from liver glycogen, lactate, and glycerol, distinct from humans. Several organs spared glucose, a process that broke down in exhausted mice despite concomitant hypoglycemia. Proteolysis increased markedly, also divergent from humans. Fatty acid oxidation dominated during fasted exercise. Ketone production and oxidation rose rapidly, seemingly driven by a hepatic bottleneck caused by gluconeogenesis-induced cataplerotic stress. Altered fuel consumption was observed in organs not directly involved in muscle contraction, including the pancreas and brown fat. Several futile cycles surprisingly persisted during exercise, despite their energy cost. In sum, we provide a comprehensive, integrated, holistic, and quantitative accounting of metabolism during exercise in an intact organism.
    Keywords:  TCA cycle; circulating metabolites; energy metabolism; exercise; in vivo flux quantification; isotope tracing; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.010
  3. Nat Metab. 2024 Oct 15.
    Itaconate drives mtRNA-mediated type I interferon production through inhibition of succinate dehydrogenase.
    Shane M O'Carroll, Christian G Peace, Juliana E Toller-Kawahisa, Yukun Min, Alexander Hooftman, Sara Charki, Louise Kehoe, Maureen J O'Sullivan, Aline Zoller, Anne F Mcgettrick, Emily A Day, Maria Simarro, Neali Armstrong, Justin P Annes, Luke A J O'Neill.
      Itaconate is one of the most highly upregulated metabolites in inflammatory macrophages and has been shown to have immunomodulatory properties. Here, we show that itaconate promotes type I interferon production through inhibition of succinate dehydrogenase (SDH). Using pharmacological and genetic approaches, we show that SDH inhibition by endogenous or exogenous itaconate leads to double-stranded mitochondrial RNA (mtRNA) release, which is dependent on the mitochondrial pore formed by VDAC1. In addition, the double-stranded RNA sensors MDA5 and RIG-I are required for IFNβ production in response to SDH inhibition by itaconate. Collectively, our data indicate that inhibition of SDH by itaconate links TCA cycle modulation to type I interferon production through mtRNA release.
    DOI:  https://doi.org/10.1038/s42255-024-01145-1
  4. Nat Metab. 2024 Oct 18.
    Farnesyl pyrophosphate potentiates dendritic cell migration in autoimmunity through mitochondrial remodelling.
    Xiaomin Zhang, Yali Chen, Geng Sun, Yankang Fei, Ha Zhu, Yanfang Liu, Junyan Dan, Chunzhen Li, Xuetao Cao, Juan Liu.
      Cellular metabolism modulates dendritic cell (DC) maturation and activation. Migratory dendritic cells (mig-DCs) travelling from the tissues to draining lymph nodes (dLNs) are critical for instructing adaptive immune responses. However, how lipid metabolites influence mig-DCs in autoimmunity remains elusive. Here, we demonstrate that farnesyl pyrophosphate (FPP), an intermediate of the mevalonate pathway, accumulates in mig-DCs derived from mice with systemic lupus erythematosus (SLE). FPP promotes mig-DC survival and germinal centre responses in the dLNs by coordinating protein geranylgeranylation and mitochondrial remodelling. Mechanistically, FPP-dependent RhoA geranylgeranylation promotes mitochondrial fusion and oxidative respiration through mitochondrial RhoA-MFN interaction, which subsequently facilitates the resolution of endoplasmic reticulum stress in mig-DCs. Simvastatin, a chemical inhibitor of the mevalonate pathway, restores mitochondrial function in mig-DCs and ameliorates systemic pathogenesis in SLE mice. Our study reveals a critical role for FPP in dictating mig-DC survival by reprogramming mitochondrial structure and metabolism, providing new insights into the pathogenesis of DC-dependent autoimmune diseases.
    DOI:  https://doi.org/10.1038/s42255-024-01149-x
  5. Nat Metab. 2024 Oct 15.
    Itaconate modulates mitochondria for antiviral IFN-β.
    Thekla Cordes, Karsten Hiller.
      
    DOI:  https://doi.org/10.1038/s42255-024-01146-0
  6. J Clin Invest. 2024 Oct 01. pii: e177242. [Epub ahead of print]
    Androgen signaling restricts glutaminolysis to drive sex-specific Th17 metabolism in allergic airway inflammation.
    Nowrin U Chowdhury, Jacqueline-Yvonne Cephus, Emely Henriquez Pilier, Melissa M Wolf, Matthew Z Madden, Shelby N Kuehnle, Kaitlin E McKernan, Erin Q Jennings, Emily N Arner, Darren R Heintzman, Channing Chi, Ayaka Sugiura, Matthew T Stier, Kelsey Voss, Xiang Ye, Kennedi L Scales, Evan S Krystofiak, Vivek D Gandhi, Robert D Guzy, Katherine N Cahill, Anne I Sperling, R Stokes Peebles, Jeffrey C Rathmell, Dawn C Newcomb.
      Females have an increased prevalence of many Th17 cell-mediated diseases, including asthma. Androgen signaling decreases Th17 cell-mediated airway inflammation, and Th17 cells rely on glutaminolysis. However, it remains unclear whether androgen receptor (AR) signaling modifies glutamine metabolism to suppress Th17 cell-mediated airway inflammation. We show that Th17 cells from male humans and mice had decreased glutaminolysis compared to females, and that AR signaling attenuated Th17 cell mitochondrial respiration and glutaminolysis in mice. Using allergen-induced airway inflammation mouse models, we determined females had a selective reliance upon glutaminolysis for Th17-mediated airway inflammation, and AR signaling attenuated glutamine uptake in CD4+ T cells by reducing expression of glutamine transporters. Minimal reliance on glutamine uptake in male Th17 cells compared to female Th17 cells was also found in circulating T cells from patients with asthma. AR signaling thus attenuates glutaminolysis, demonstrating sex-specific metabolic regulation of Th17 cells with implications for Th17 or glutaminolysis targeted therapeutics.
    Keywords:  Asthma; Immunology; Pulmonology; Sex hormones; T cells
    DOI:  https://doi.org/10.1172/JCI177242
  7. Nat Metab. 2024 Oct 15.
    Cytosolic acetyl-CoA synthesis shields mitochondria from stress in brown adipocytes.
      
    DOI:  https://doi.org/10.1038/s42255-024-01152-2
  8. Cell Rep. 2024 Oct 17. pii: S2211-1247(24)01219-1. [Epub ahead of print]43(11): 114868
    PD-L1 protects tumor-associated dendritic cells from ferroptosis during immunogenic chemotherapy.
    Kaimin Xiao, Silin Zhang, Qi Peng, Yuxia Du, Xiyue Yao, Ian-Ian Ng, Haidong Tang.
      Dendritic cells (DCs) express high levels of PD-L1 in the tumor microenvironment. However, the physiological functions of PD-L1 on DCs remain incompletely understood. Here, we explored the roles of PD-L1 signaling during immunogenic chemotherapy. We found that antitumor efficacy was dramatically reduced in the absence of PD-L1 on DCs. Chemotherapy reshaped the tumor immune microenvironment, particularly the DC compartment. In the absence of PD-L1, DCs were more susceptible to the cytotoxicity induced by chemotherapy. Mechanistically, loss of PD-L1 led to the downregulation of SLC7A11, resulting in increased lipid peroxidation that caused DCs to succumb to ferroptosis and dampened antitumor immune responses. Mice with Pdl1-deficient DCs were less efficient at priming T cells during chemotherapy. In cancer patients, a higher level of PD-L1 on DCs correlated with better prognosis after immunogenic chemotherapy. Collectively, these findings reveal an underappreciated role of PD-L1 in orchestrating DC survival, which is critical during chemoimmunotherapy.
    Keywords:  CP: Cancer; CP: Immunology; PD-L1; cancer immunotherapy; dendritic cell; ferroptosis; immunogenic chemotherapy
    DOI:  https://doi.org/10.1016/j.celrep.2024.114868
  9. J Clin Invest. 2024 Oct 15. pii: e169722. [Epub ahead of print]
    Adipocyte lipin 1 expression associates with human metabolic health and regulates systemic metabolism in mice.
    Andrew LaPoint, Jason M Singer, Daniel Ferguson, Trevor M Shew, M Katie Renkemeyer, Hector H Palacios, Rachael L Field, Sireeesha Yerrathota, Roshan Kumari, Mahalakshmi Shankaran, Gordon I Smith, Jun Yoshino, Mai He, Gary J Patti, Marc K Hellerstein, Samuel Klein, E Matthew Morris, Jonathan R Brestoff, Brian N Finck, Andrew Lutkewitte.
      Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol (DAG), the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared to lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multi-omic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically-unhealthy phenotype, including liver and skeletal muscle insulin resistance, hepatic steatosis, increased hepatic de novo lipogenesis, and transcriptomic signatures of metabolically associated steatohepatitis that was exacerbated by high-fat diets. We conclude that adipocyte lipin 1-mediated lipid storage is vital for preserving adipose tissue and systemic metabolic health, and its loss predisposes mice to metabolically associated steatohepatitis.
    Keywords:  Diabetes; Hepatology; Insulin signaling; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI169722
  10. Nature. 2024 Oct 16.
    Selective utilization of glucose metabolism guides mammalian gastrulation.
    Dominica Cao, Jenna Bergmann, Liangwen Zhong, Anupama Hemalatha, Chaitanya Dingare, Tyler Jensen, Andy L Cox, Valentina Greco, Benjamin Steventon, Berna Sozen.
      The prevailing dogma for morphological patterning in developing organisms argues that the combined inputs of transcription factor networks and signalling morphogens alone generate spatially and temporally distinct expression patterns. However, metabolism has also emerged as a critical developmental regulator1-10, independent of its functions in energy production and growth. The mechanistic role of nutrient utilization in instructing cellular programmes to shape the in vivo developing mammalian embryo remains unknown. Here we reveal two spatially resolved, cell-type- and stage-specific waves of glucose metabolism during mammalian gastrulation by using single-cell-resolution quantitative imaging of developing mouse embryos, stem cell models and embryo-derived tissue explants. We identify that the first spatiotemporal wave of glucose metabolism occurs through the hexosamine biosynthetic pathway to drive fate acquisition in the epiblast, and the second wave uses glycolysis to guide mesoderm migration and lateral expansion. Furthermore, we demonstrate that glucose exerts its influence on these developmental processes through cellular signalling pathways, with distinct mechanisms connecting glucose with the ERK activity in each wave. Our findings underscore that-in synergy with genetic mechanisms and morphogenic gradients-compartmentalized cellular metabolism is integral in guiding cell fate and specialized functions during development. This study challenges the view of the generic and housekeeping nature of cellular metabolism, offering valuable insights into its roles in various developmental contexts.
    DOI:  https://doi.org/10.1038/s41586-024-08044-1
  11. Cell Stem Cell. 2024 Oct 14. pii: S1934-5909(24)00324-2. [Epub ahead of print]
    A distinct metabolic and epigenetic state drives trained immunity in HSC-derived macrophages from autoimmune mice.
    Taylor S Mills, Bailee Kain, Matt A Burchill, Etienne Danis, Erin D Lucas, Rachel Culp-Hill, Courtney M Cowan, Wolfgang E Schleicher, Sweta B Patel, Brandon T Tran, Ruoqiong Cao, Andrew Goodspeed, Sarah Ferrara, Shaun Bevers, Beth A Jirón Tamburini, James R Roede, Angelo D'Alessandro, Katherine Y King, Eric M Pietras.
      Here, we investigate the contribution of long-term hematopoietic stem cells (HSCsLT) to trained immunity (TI) in the setting of chronic autoimmune disease. Using a mouse model of systemic lupus erythematosus (SLE), we show that bone marrow-derived macrophages (BMDMs) from autoimmune mice exhibit hallmark features of TI, including increased Mycobacterium avium killing and inflammatory cytokine production, which are mechanistically linked to increased glycolytic metabolism. We show that HSCs from autoimmune mice constitute a transplantable, long-term reservoir for macrophages that exhibit the functional properties of TI. However, these BMDMs exhibit reduced glycolytic activity and chromatin accessibility at metabolic genes while retaining elevated expression of TI-associated transcriptional regulators. Hence, HSC exposed to autoimmune inflammation can give rise to macrophages in which the functional and metabolic properties of TI are decoupled. Our data support a model in which TI is characterized by a spectrum of molecular and metabolic states driving augmented immune function.
    Keywords:  autoimmune disease; bone marrow-derived macrophage; hematopoietic stem cell; inflammation; metabolism; trained immunity
    DOI:  https://doi.org/10.1016/j.stem.2024.09.010
  12. Nat Commun. 2024 Oct 17. 15(1): 8971
    Methionine-SAM metabolism-dependent ubiquinone synthesis is crucial for ROS accumulation in ferroptosis induction.
    Chaoyi Xia, Pinghui Peng, Wenxia Zhang, Xiyue Xing, Xin Jin, Jianlan Du, Wanting Peng, Fengqi Hao, Zhexuan Zhao, Kejian Dong, Miaomiao Tian, Yunpeng Feng, Xueqing Ba, Min Wei, Yang Wang.
      Ferroptosis is a cell death modality in which iron-dependent lipid peroxides accumulate on cell membranes. Cysteine, a limiting substrate for the glutathione system that neutralizes lipid peroxidation and prevents ferroptosis, can be converted by cystine reduction or synthesized from methionine. However, accumulating evidence shows methionine-based cysteine synthesis fails to effectively rescue intracellular cysteine levels upon cystine deprivation and is unable to inhibit ferroptosis. Here, we report that methionine-based cysteine synthesis is tissue-specific. Unexpectedly, we find that rather than inhibiting ferroptosis, methionine in fact plays an essential role during cystine deprivation-induced ferroptosis. Methionine-derived S-adenosylmethionine (SAM) contributes to methylation-dependent ubiquinone synthesis, which leads to lipid peroxides accumulation and subsequent ferroptosis. Moreover, SAM supplementation synergizes with Imidazole Ketone Erastin in a tumor growth suppression mouse model. Inhibiting the enzyme that converts methionine to SAM protects heart tissue from Doxorubicin-induced and ferroptosis-driven cardiomyopathy. This study broadens our understanding about the intersection of amino acid metabolism and ferroptosis regulation, providing insight into the underlying mechanisms and suggesting the methionine-SAM axis is a promising therapeutic strategy to treat ferroptosis-related diseases.
    DOI:  https://doi.org/10.1038/s41467-024-53380-5
  13. Nitric Oxide. 2024 Oct 15. pii: S1089-8603(24)00136-8. [Epub ahead of print]
    Generation and characterization of a conditional eNOS knock out mouse model for cell-specific reactivation of eNOS in gain-of-function studies.
    Anthea LoBue, Zhixin Li, Sophia K Heuser, Junjie Li, Francesca Leo, Lukas Vornholz, Luke S Dunaway, Tatsiana Suvorava, Brant E Isakson, Miriam M Cortese-Krott.
      Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) in the vessel wall regulates blood pressure and cardiovascular hemodynamics. In this study, we generated conditional eNOS knock out (KO) mice characterized by a duplicated/inverted exon 2 flanked with two pairs of loxP regions (eNOSinv/inv); a Cre-recombinase activity induces cell-specific reactivation of eNOS, as a result of a flipping of the inverted exon 2 (eNOSfl). This work aimed to test the efficiency of the Cre-mediated cell-specific recombination and the resulting eNOS expression/function. As proof of concept, we crossed eNOSinv/inv mice with DeleterCrepos (DelCrepos) mice, expressing Cre recombinase in all cells. We generated heterozygous eNOSfl/inv or homozygous eNOSfl/fl mice, and eNOSinv/inv littermate mice. We found that (1) both eNOSfl/fl and eNOSfl/inv mice express eNOS and the overall expression level depends on the number of mutated alleles, while eNOSinv/inv mice did not show any eNOS expression. (2) Vascular endothelial function was restored in eNOSfl/fl and eNOSfl/inv mice, as determined by ACh-dependent vasodilation of aortic rings. (3) Cre-dependent reactivation of eNOS in eNOSfl/fl and eNOSfl/inv mice rescued eNOSinv/inv (phenotypically global eNOS KO) mice from hypertension. These findings demonstrate that eNOS expression is restored in eNOSfl/fl mice at comparable physiological levels of WT mice, and its functional activity is independent on the number of the reactivated alleles. Therefore, eNOSinv/inv mice are a useful model for studying the effects of conditional reactivation of eNOS and gene dosage effects in specific cells for gain-of-function studies.
    Keywords:  Cre/LoxP system; eNOS; eNOS reactivation; nitric oxide
    DOI:  https://doi.org/10.1016/j.niox.2024.10.009
  14. EMBO J. 2024 Oct 17.
    Macropinocytosis mediates resistance to loss of glutamine transport in triple-negative breast cancer.
    Kanu Wahi, Natasha Freidman, Qian Wang, Michelle Devadason, Lake-Ee Quek, Angel Pang, Larissa Lloyd, Mark Larance, Fabio Zanini, Kate Harvey, Sandra O'Toole, Yi Fang Guan, Jeff Holst.
      Triple-negative breast cancer (TNBC) metabolism and cell growth uniquely rely on glutamine uptake by the transporter ASCT2. Despite previous data reporting cell growth inhibition after ASCT2 knockdown, we here show that ASCT2 CRISPR knockout is tolerated by TNBC cell lines. Despite the loss of a glutamine transporter and low rate of glutamine uptake, intracellular glutamine steady-state levels were increased in ASCT2 knockout compared to control cells. Proteomics analysis revealed upregulation of macropinocytosis, reduction in glutamine efflux and increased glutamine synthesis in ASCT2 knockout cells. Deletion of ASCT2 in the TNBC cell line HCC1806 induced a strong increase in macropinocytosis across five ASCT2 knockout clones, compared to a modest increase in ASCT2 knockdown. In contrast, ASCT2 knockout impaired cell proliferation in the non-macropinocytic HCC1569 breast cancer cells. These data identify macropinocytosis as a critical secondary glutamine acquisition pathway in TNBC and a novel resistance mechanism to strategies targeting glutamine uptake alone. Despite this adaptation, TNBC cells continue to rely on glutamine metabolism for their growth, providing a rationale for targeting of more downstream glutamine metabolism components.
    Keywords:  ASCT2; Glutamine Metabolism; Macropinocytosis; Metabolomics; Triple-Negative Breast Cancer
    DOI:  https://doi.org/10.1038/s44318-024-00271-6
  15. Nat Commun. 2024 Oct 16. 15(1): 8936
    Thermal proteome profiling reveals fructose-1,6-bisphosphate as a phosphate donor to activate phosphoglycerate mutase 1.
    Yanling Zhang, Yafei Cao, Xia Wu, Zhenghui Chen, Bowen Chen, Anhui Wang, Yanshen Guo, Wei Chen, Ruolan Xue, Zihua Liu, Yuanpei Li, Tian Li, Ruiqin Cheng, Ning Zhou, Jing Li, Yuan Liu, Xiaohui Zhao, Huixin Luo, Ming Xu, Houhua Li, Yiqun Geng.
      Deep understanding of sugar metabolite-protein interactions should provide implications on sugar metabolic reprogramming in human physiopathology. Although tremendous efforts have been made for determining individual event, global profiling of such interactome remains challenging. Here we describe thermal proteome profiling of glycolytic metabolite fructose-1,6-bisphosphate (FBP)-interacting proteins. Our results reveal a chemical signaling role of FBP which acts as a phosphate donor to activate phosphoglycerate mutase 1 (PGAM1) and contribute an intrapathway feedback for glycolysis and cell proliferation. At molecular level, FBP donates either C1-O-phosphate or C6-O-phosphate to the catalytic histidine of PGAM1 to form 3-phosphate histidine (3-pHis) modification. Importantly, structure-activity relationship studies facilitate the discovery of PGAM1 orthostatic inhibitors which can potentially restrain cancer cell proliferation. Collectively we have profiled a spectrum of FBP interactome, and discovered a unique covalent signaling function of FBP that supports Warburg effect via histidine phosphorylation which inspires the development of pharmacological tools targeting sugar metabolism.
    DOI:  https://doi.org/10.1038/s41467-024-53238-w
  16. Immunity. 2024 Oct 11. pii: S1074-7613(24)00459-X. [Epub ahead of print]
    Retinoic acid and TGF-β orchestrate organ-specific programs of tissue residency.
    Andreas Obers, Tobias Poch, Grace Rodrigues, Susan N Christo, Luke C Gandolfo, Raissa Fonseca, Ali Zaid, Joey En Yu Kuai, Hongjin Lai, Pirooz Zareie, Marina H Yakou, Lachlan Dryburgh, Thomas N Burn, James Dosser, Frank A Buquicchio, Caleb A Lareau, Calum Walsh, Louise Judd, Maria Rafailia Theodorou, Katharina Gutbrod, Peter Dörmann, Jenny Kingham, Tim Stinear, Axel Kallies, Jan Schroeder, Scott N Mueller, Simone L Park, Terence P Speed, Ansuman T Satpathy, Tri Giang Phan, Christoph Wilhelm, Colby Zaph, Maximilien Evrard, Laura K Mackay.
      Tissue-resident memory T (TRM) cells are integral to tissue immunity, persisting in diverse anatomical sites where they adhere to a common transcriptional framework. How these cells integrate distinct local cues to adopt the common TRM cell fate remains poorly understood. Here, we show that whereas skin TRM cells strictly require transforming growth factor β (TGF-β) for tissue residency, those in other locations utilize the metabolite retinoic acid (RA) to drive an alternative differentiation pathway, directing a TGF-β-independent tissue residency program in the liver and synergizing with TGF-β to drive TRM cells in the small intestine. We found that RA was required for the long-term maintenance of intestinal TRM populations, in part by impeding their retrograde migration. Moreover, enhanced RA signaling modulated TRM cell phenotype and function, a phenomenon mirrored in mice with increased microbial diversity. Together, our findings reveal RA as a fundamental component of the host-environment interaction that directs immunosurveillance in tissues.
    Keywords:  CD8(+) T cells; IEL; T cell memory; TRM cells; dirty mice; mucosal immunity; retinoic acid; tissue-resident memory T cells; transforming growth factor beta
    DOI:  https://doi.org/10.1016/j.immuni.2024.09.015
  17. J Exp Med. 2024 Nov 04. pii: e20240992. [Epub ahead of print]221(11):
    Phosphatidylserine phospholipase A1 enables GPR34-dependent immune cell accumulation in the peritoneal cavity.
    Hanson Tam, Ying Xu, Jinping An, Torsten Schöneberg, Angela Schulz, Jagan R Muppidi, Jason G Cyster.
      The peritoneal cavity (PerC) is an important site for immune responses to infection and cancer metastasis. Yet few ligand-receptor axes are known to preferentially govern immune cell accumulation in this compartment. GPR34 is a lysophosphatidylserine (lysoPS)-responsive receptor that frequently harbors gain-of-function mutations in mucosa-associated B cell lymphoma. Here, we set out to test the impact of a GPR34 knock-in (KI) allele in the B-lineage. We report that GPR34 KI promotes the PerC accumulation of plasma cells (PC) and memory B cells (MemB). These KI cells migrate robustly to lysoPS ex vivo, and the KI allele synergizes with a Bcl2 transgene to promote MemB but not PC accumulation. Gene expression and labeling studies reveal that GPR34 KI enhances PerC MemB proliferation. Both KI PC and MemB are specifically enriched at the omentum, a visceral adipose tissue containing fibroblasts that express the lysoPS-generating PLA1A enzyme. Adoptive transfer and chimera experiments revealed that KI PC and MemB maintenance in the PerC is dependent on stromal PLA1A. These findings provide in vivo evidence that PLA1A produces lysoPS that can regulate GPR34-mediated immune cell accumulation at the omentum.
    DOI:  https://doi.org/10.1084/jem.20240992
  18. Sci Immunol. 2024 Oct 18. 9(100): eadg6453
    The acid-sensing receptor GPR65 on tumor macrophages drives tumor growth in obesity.
    Sreya Bagchi, Robert Yuan, Han-Li Huang, Weiruo Zhang, David Kung-Chun Chiu, Hyungjoo Kim, Sophia L Cha, Lorna Tolentino, Joshua Lowitz, Yilin Liu, Anna Moshnikova, Oleg Andreev, Sylvia Plevritis, Edgar G Engleman.
      Multiple cancers, including colorectal cancer (CRC), are more frequent and often more aggressive in individuals with obesity. Here, we showed that macrophages accumulated within tumors of patients with obesity and CRC and in obese CRC mice and that they promoted accelerated tumor growth. These changes were initiated by oleic acid accumulation and subsequent tumor cell-derived acid production and were driven by macrophage signaling through the acid-sensing receptor GPR65. We found a similar role for GPR65 in hepatocellular carcinoma (HCC) in obese mice. Tumors in patients with obesity and CRC or HCC also exhibited increased GPR65 expression, suggesting that the mechanism revealed here may contribute to tumor growth in a range of obesity-associated cancers and represent a potential therapeutic target.
    DOI:  https://doi.org/10.1126/sciimmunol.adg6453
  19. Cell Death Dis. 2024 Oct 14. 15(10): 746
    A sphingolipid rheostat controls apoptosis versus apical cell extrusion as alternative tumour-suppressive mechanisms.
    Joy Armistead, Sebastian Höpfl, Pierre Goldhausen, Andrea Müller-Hartmann, Evelin Fahle, Julia Hatzold, Rainer Franzen, Susanne Brodesser, Nicole E Radde, Matthias Hammerschmidt.
      Evasion of cell death is a hallmark of cancer, and consequently the induction of cell death is a common strategy in cancer treatment. However, the molecular mechanisms regulating different types of cell death are poorly understood. We have formerly shown that in the epidermis of hypomorphic zebrafish hai1a mutant embryos, pre-neoplastic transformations of keratinocytes caused by unrestrained activity of the type II transmembrane serine protease Matriptase-1 heal spontaneously. This healing is driven by Matriptase-dependent increased sphingosine kinase (SphK) activity and sphingosine-1-phosphate (S1P)-mediated keratinocyte loss via apical cell extrusion. In contrast, amorphic hai1afr26 mutants with even higher Matriptase-1 and SphK activity die within a few days. Here we show that this lethality is not due to epidermal carcinogenesis, but to aberrant tp53-independent apoptosis of keratinocytes caused by increased levels of pro-apoptotic C16 ceramides, sphingolipid counterparts to S1P within the sphingolipid rheostat, which severely compromises the epidermal barrier. Mathematical modelling of sphingolipid rheostat homeostasis, combined with in vivo manipulations of components of the rheostat or the ceramide de novo synthesis pathway, indicate that this unexpected overproduction of ceramides is caused by a negative feedback loop sensing ceramide levels and controlling ceramide replenishment via de novo synthesis. Therefore, despite their initial decrease due to increased conversion to S1P, ceramides eventually reach cell death-inducing levels, making transformed pre-neoplastic keratinocytes die even before they are extruded, thereby abrogating the normally barrier-preserving mode of apical live cell extrusion. Our results offer an in vivo perspective of the dynamics of sphingolipid homeostasis and its relevance for epithelial cell survival versus cell death, linking apical cell extrusion and apoptosis. Implications for human carcinomas and their treatments are discussed.
    DOI:  https://doi.org/10.1038/s41419-024-07134-2
  20. J Biol Chem. 2024 Oct 14. pii: S0021-9258(24)02392-5. [Epub ahead of print] 107890
    Oncogenic accumulation of cysteine promotes cancer cell proliferation by regulating the translation of D-type cyclins.
    Yumi Okano, Tomoaki Yamauchi, Runa Fukuzaki, Akito Tsuruta, Yuya Yoshida, Yuya Tsurudome, Kentaro Ushijima, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo.
      Malignant cells exhibit a high demand for amino acids to sustain their abnormal proliferation. Particularly, the intracellular accumulation of cysteine is often observed in cancer cells. Previous studies have shown that deprivation of intracellular cysteine in cancer cells results in the accumulation of lipid peroxides in the plasma membrane and induction of ferroptotic cell death, indicating that cysteine plays a critical role in the suppression of ferroptosis. Herein, we found that the oncogenic accumulation of cysteine also contributes to cancer cell proliferation by promoting the cell cycle progression, which is independent of its suppressive effect on ferroptosis. The growth ability of four types of cancer cells, including murine hepatocarcinoma cells, but not of primary hepatocytes, were dependent on the exogenous supply of cysteine. Deprivation of intracellular cysteine in cancer cells induced cell cycle arrest at the G0/G1 phase, accompanied by a decrease in the expression of cyclin D1 and D2 proteins. The cysteine deprivation-induced decrease in D-type cyclin expression was associated with the upregulation of eukaryotic translation initiation factor 4E binding protein (4E-BP1), which represses the translation of cyclin D1 and D2 proteins by binding to eukaryotic translation initiation factor 4E (eIF4E). Similar results were observed in hepatocarcinoma cells treated with erastin, an xCT inhibitor. These findings reveal an unappreciated role of cysteine in regulating the growth of malignant cancer cells and deepen our understanding of the cytotoxic effect of xCT inhibitor to prevent cancer cell proliferation.
    DOI:  https://doi.org/10.1016/j.jbc.2024.107890
  21. Mol Cell. 2024 Oct 17. pii: S1097-2765(24)00703-2. [Epub ahead of print]84(20): 3979-3996.e9
    A TBK1-independent primordial function of STING in lysosomal biogenesis.
    Bo Lv, William A Dion, Haoxiang Yang, Jinrui Xun, Do-Hyung Kim, Bokai Zhu, Jay Xiaojun Tan.
      Stimulator of interferon genes (STING) is activated in many pathophysiological conditions, leading to TBK1-dependent interferon production in higher organisms. However, primordial functions of STING independent of TBK1 are poorly understood. Here, through proteomics and bioinformatics approaches, we identify lysosomal biogenesis as an unexpected function of STING. Transcription factor EB (TFEB), an evolutionarily conserved regulator of lysosomal biogenesis and host defense, is activated by STING from multiple species, including humans, mice, and frogs. STING-mediated TFEB activation is independent of TBK1, but it requires STING trafficking and its conserved proton channel. GABARAP lipidation, stimulated by the channel of STING, is key for STING-dependent TFEB activation. STING stimulates global upregulation of TFEB-target genes, mediating lysosomal biogenesis and autophagy. TFEB supports cell survival during chronic sterile STING activation, a common condition in aging and age-related diseases. These results reveal a primordial function of STING in the biogenesis of lysosomes, essential organelles in immunity and cellular stress resistance.
    Keywords:  STING; STING channel; TBK1; TFE3; TFEB; autophagy; cGAS; chronic STING signaling; lysosome
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.026
  22. J Lipid Res. 2024 Oct 11. pii: S0022-2275(24)00177-9. [Epub ahead of print] 100672
    Palmitoleate protects against Lipopolysaccharide-induced Inflammation and Inflammasome Activity.
    Prakash Kumar Sahoo, Aiswariya Ravi, Baolong Liu, Jiujiu Yu, Sathish Kumar Natarajan.
      Inflammation is part of natural immune defense mechanism against any form of infection or injury. However, prolonged inflammation could perturb cell homeostasis and contribute to the development of metabolic and inflammatory diseases including maternal obesity, diabetes, cardiovascular diseases, and metabolic dysfunction-associated steatotic liver diseases. Polyunsaturated fatty acids have been shown to mitigate inflammatory response by generating specialized pro-resolving lipid mediators which take part in resolution of inflammation. Here, we show that palmitoleate, an omega-7 monounsaturated fatty acid exerts anti-inflammatory properties in response to lipopolysaccharide (LPS)-mediated inflammation. Exposure of bone-marrow derived macrophages (BMDMs) to LPS or TNFα induces robust increase in the expression of pro-inflammatory cytokines and supplementation of palmitoleate inhibited LPS-mediated upregulation of pro-inflammatory cytokines. We also observed that palmitoleate was able to block LPS+ATP-induced inflammasome activation mediated cleavage of pro-caspase 1 and pro-interleukin (IL)-1β. Further, treatment of palmitoleate protects against LPS-induced inflammation in human THP-1 derived macrophages and trophoblasts. Co-exposure of LPS and palmitate (saturated free fatty acid) induces inflammasome and cell death in BMDMs, however, treatment of palmitoleate blocked LPS and palmitate-induced cell death in BMDMs. Further, LPS and palmitate together results in the activation of mitogen activated protein kinases (MAPK) and pretreatment of palmitoleate inhibited the activation of MAPKs and nuclear translocation of nuclear factor kappa B (NF-kB) in BMDMs. In conclusion, palmitoleate shows anti-inflammatory properties against LPS-induced inflammation and LPS+palmitate/ATP-induced inflammasome activity and cell death.
    Keywords:  Mono-unsaturated fatty acids; macrophages; mitogen-activated protein kinase; obesity; placenta; pregnancy; trophoblasts
    DOI:  https://doi.org/10.1016/j.jlr.2024.100672
  23. Cell Rep. 2024 Oct 10. pii: S2211-1247(24)01198-7. [Epub ahead of print]43(10): 114847
    Visualizing the spatial organization of monocytes, interstitial macrophages, and tissue-specific macrophages in situ.
    Maxime Petit, Eléonore Weber-Delacroix, François Lanthiez, Sandrine Barthélémy, Noëlline Guillou, Marina Firpion, Olivia Bonduelle, David A Hume, Christophe Combadière, Alexandre Boissonnas.
      Tissue-resident mononuclear phagocytes (MPs) are an abundant cell population whose localization in situ reflects their identity. To enable assessment of their heterogeneity, we developed the red/green/blue (RGB)-Mac mouse based upon combinations of Cx3cr1 and Csf1r reporter transgenes, providing a complete visualization of their spatial organization in situ. 3D-multi-photon imaging for spatial mapping and spectral cytometry employing the three markers in combination distinguished tissue-associated monocytes, tissue-specific macrophages, and three subsets of connective-tissue-associated MPs, including CCR2+ monocyte-derived cell, CX3CR1+, and FOLR2+ interstitial subsets, associated with distinct sub-anatomic territories. These populations were selectively reduced by blockade of CSF1, CSF2, CCR2, and CX3CR1 and efficiently reconstitute their spatial distribution after transient myelo-ablation, suggesting an autonomous regulatory environment. Our findings emphasize the organization of the MP compartment at the sub-anatomic level under steady-state conditions, thereby providing a holistic understanding of their relative heterogeneity across different tissues.
    Keywords:  CP: Immunology; macrophage niches; monocytes; structural imaging; tissue-resident macrophage
    DOI:  https://doi.org/10.1016/j.celrep.2024.114847
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