bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024–11–03
nineteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones.
  2. Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase.
  3. Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity.
  4. Obesity-associated intratumoral acidity promotes pro-tumorigenic macrophages.
  5. Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells.
  6. Nanoparticle-based itaconate treatment recapitulates low-cholesterol/low-fat diet-induced atherosclerotic plaque resolution.
  7. TrkB signalling regulates dopamine circuits and motor function through metabolic pathways.
  8. Amino acid is a major carbon source for hepatic lipogenesis.
  9. ASCL1 regulates and cooperates with FOXA2 to drive terminal neuroendocrine phenotype in prostate cancer.
  10. The GPCR adaptor protein Norbin controls the trafficking of C5aR1 and CXCR4 in mouse neutrophils.
  11. Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.
  12. Membrane potential stimulates ADP import and ATP export by the mitochondrial ADP/ATP carrier due to its positively charged binding site.
  13. Ovarian cancer-derived IL-4 promotes immunotherapy resistance.
  14. Impaired activation of succinate-induced type 2 immunity and secretory cell production in the small intestines of Ptk6-/- male mice.
  15. Protumoral lipid droplet-loaded macrophages are enriched in human glioblastoma and can be therapeutically targeted.
  16. N-acetyltransferase 10 is implicated in the pathogenesis of cycling T cell-mediated autoimmune and inflammatory disorders in mice.
  17. Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway.
  18. Metabolic programs drive function of therapeutic NK cells in hypoxic tumor environments.
  19. Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells.
  1. Cell Metab. 2024 Oct 25. pii: S1550-4131(24)00409-1. [Epub ahead of print]
    A hierarchical hepatic de novo lipogenesis substrate supply network utilizing pyruvate, acetate, and ketones.
    Adam J Rauckhorst, Ryan D Sheldon, Daniel J Pape, Adnan Ahmed, Kelly C Falls-Hubert, Ronald A Merrill, Reid F Brown, Kshitij Deshmukh, Thomas A Vallim, Stanislaw Deja, Shawn C Burgess, Eric B Taylor.
      Hepatic de novo lipogenesis (DNL) is a fundamental physiologic process that is often pathogenically elevated in metabolic disease. Treatment is limited by incomplete understanding of the metabolic pathways supplying cytosolic acetyl-CoA, the obligate precursor to DNL, including their interactions and proportional contributions. Here, we combined extensive 13C tracing with liver-specific knockout of key mitochondrial and cytosolic proteins mediating cytosolic acetyl-CoA production. We show that the mitochondrial pyruvate carrier (MPC) and ATP-citrate lyase (ACLY) gate the major hepatic lipogenic acetyl-CoA production pathway, operating in parallel with acetyl-CoA synthetase 2 (ACSS2). Given persistent DNL after mitochondrial citrate carrier (CiC) and ACSS2 double knockout, we tested the contribution of exogenous and leucine-derived acetoacetate to acetoacetyl-CoA synthetase (AACS)-dependent DNL. CiC knockout increased acetoacetate-supplied hepatic acetyl-CoA production and DNL, indicating that ketones function as mitochondrial-citrate reciprocal DNL precursors. By delineating a mitochondrial-cytosolic DNL substrate supply network, these findings may inform strategies to therapeutically modulate DNL.
    Keywords:  AACS; ACLY; ACSS2; ATP-citrate lyase; CiC; DNL; MPC; acetoacetyl-CoA synthetase; acetyl-CoA synthetase 2; de novo lipogenesis; liver; metabolomics; mitochondrial citrate carrier; mitochondrial pyruvate carrier; stable isotope tracers
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.013
  2. Cell Metab. 2024 Oct 26. pii: S1550-4131(24)00410-8. [Epub ahead of print]
    Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase.
    Joyce Y Liu, Ramya S Kuna, Laura V Pinheiro, Phuong T T Nguyen, Jaclyn E Welles, Jack M Drummond, Nivitha Murali, Prateek Sharma, Julianna G Supplee, Mia Shiue, Steven Zhao, Aimee T Farria, Avi Kumar, Mauren L Ruchhoeft, Christina Demetriadou, Daniel S Kantner, Adam Chatoff, Emily Megill, Paul M Titchenell, Nathaniel W Snyder, Christian M Metallo, Kathryn E Wellen.
      ATP citrate lyase (ACLY) synthesizes acetyl-CoA for de novo lipogenesis (DNL), which is elevated in metabolic dysfunction-associated steatotic liver disease. Hepatic ACLY is inhibited by the LDL-cholesterol-lowering drug bempedoic acid (BPA), which also improves steatosis in mice. While BPA potently suppresses hepatic DNL and increases fat catabolism, it is unclear if ACLY is its primary molecular target in reducing liver triglyceride. We show that on a Western diet, loss of hepatic ACLY alone or together with the acetyl-CoA synthetase ACSS2 unexpectedly exacerbates steatosis, linked to reduced PPARα target gene expression and fatty acid oxidation. Importantly, BPA treatment ameliorates Western diet-mediated triacylglyceride accumulation in both WT and liver ACLY knockout mice, indicating that its primary effects on hepatic steatosis are ACLY independent. Together, these data indicate that hepatic ACLY plays an unexpected role in restraining diet-dependent lipid accumulation and that BPA exerts substantial effects on hepatic lipid metabolism independently of ACLY.
    Keywords:  ACLY; ACSS2; PPARα; bempedoic acid; lipid metabolism; metabolic dysfunction-associated steatotic liver disease
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.014
  3. Oncogene. 2024 Oct 29.
    Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity.
    Joanne D Tejero, Rebecca S Hesterberg, Stanislav Drapela, Didem Ilter, Devesh Raizada, Felicia Lazure, Hossein Kashfi, Min Liu, Leonardo Silvane, Dorina Avram, Juan Fernández-García, John M Asara, Sarah-Maria Fendt, John L Cleveland, Ana P Gomes.
      Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8+ T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8+ T cell immunity. Treatment of primary CD8+ T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8+ T cells and decreased their effector functions, which drove the suppression of anti-tumor immunity in vitro and in vivo. Mechanistically, MMA-induced CD8+ T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.
    DOI:  https://doi.org/10.1038/s41388-024-03191-1
  4. Nat Rev Immunol. 2024 Oct 28.
    Obesity-associated intratumoral acidity promotes pro-tumorigenic macrophages.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-024-01110-9
  5. Nat Commun. 2024 Oct 29. 15(1): 9337
    Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells.
    Han-Ying Huang, Yan-Zhou Chen, Chuang Zhao, Xin-Nan Zheng, Kai Yu, Jia-Xing Yue, Huai-Qiang Ju, Yan-Xia Shi, Lin Tian.
      Inflammatory signals lead to recruitment of circulating monocytes and induce their differentiation into pro-inflammatory macrophages. Therefore, whether blocking inflammatory monocytes can mitigate disease progression is being actively evaluated. Here, we employ multiple lineage-tracing models and show that monocyte-derived macrophages (mo-mac) are the major population of immunosuppressive, liver metastasis-associated macrophages (LMAM), while the proportion of Kupffer cells (KC) as liver-resident macrophages is diminished in metastatic nodules. Paradoxically, genetic ablation of mo-macs results in only a marginal decrease in LMAMs. Using a proliferation-recording system and a KC-tracing model in a monocyte-deficient background, we find that LMAMs can be replenished either via increased local macrophage proliferation or by promoting KC infiltration. In the latter regard, KCs undergo transient proliferation and exhibit substantial phenotypic and functional alterations through epigenetic reprogramming following the vacating of macrophage niches by monocyte depletion. Our data thus suggest that a simultaneous blockade of monocyte recruitment and macrophage proliferation may effectively target immunosuppressive myelopoiesis and reprogram the microenvironment towards an immunostimulatory state.
    DOI:  https://doi.org/10.1038/s41467-024-53659-7
  6. Cell Rep. 2024 Oct 27. pii: S2211-1247(24)01262-2. [Epub ahead of print]43(11): 114911
    Nanoparticle-based itaconate treatment recapitulates low-cholesterol/low-fat diet-induced atherosclerotic plaque resolution.
    Natalie E Hong, Alice Chaplin, Lin Di, Anastasia Ravodina, Graham H Bevan, Huiyun Gao, Courteney Asase, Roopesh Singh Gangwar, Mark J Cameron, Matthew Mignery, Olga Cherepanova, Aloke V Finn, Lalitha Nayak, Andrew A Pieper, Andrei Maiseyeu.
      Current pharmacologic treatments for atherosclerosis do not completely protect patients; additional protection can be achieved by dietary modifications, such as a low-cholesterol/low-fat diet (LCLFD), that mediate plaque stabilization and inflammation reduction. However, this lifestyle modification can be challenging for patients. Unfortunately, incomplete understanding of the underlying mechanisms has thwarted efforts to mimic the protective effects of a LCLFD. Here, we report that the tricarboxylic acid cycle intermediate itaconate (ITA), produced by plaque macrophages, is key to diet-induced plaque resolution. ITA is produced by immunoresponsive gene 1 (IRG1), which we observe is highly elevated in myeloid cells of vulnerable plaques and absent from early or stable plaques in mice and humans. We additionally report development of an ITA-conjugated lipid nanoparticle that accumulates in plaque and bone marrow myeloid cells, epigenetically reduces inflammation via H3K27ac deacetylation, and reproduces the therapeutic effects of LCLFD-induced plaque resolution in multiple atherosclerosis models.
    Keywords:  ApoE(−/−) mice; CP: Immunology; TCA cycle; atherosclerosis; cholesterol; itaconate; nanoparticle; plaque resolution
    DOI:  https://doi.org/10.1016/j.celrep.2024.114911
  7. Nat Metab. 2024 Oct 28.
    TrkB signalling regulates dopamine circuits and motor function through metabolic pathways.
      
    DOI:  https://doi.org/10.1038/s42255-024-01154-0
  8. Cell Metab. 2024 Oct 22. pii: S1550-4131(24)00397-8. [Epub ahead of print]
    Amino acid is a major carbon source for hepatic lipogenesis.
    Yilie Liao, Qishan Chen, Lei Liu, Haipeng Huang, Jingyun Sun, Xiaojie Bai, Chenchen Jin, Honghao Li, Fangfang Sun, Xia Xiao, Yahong Zhang, Jia Li, Weiping Han, Suneng Fu.
      Increased de novo lipogenesis is a hallmark of metabolic dysfunction-associated steatotic liver disease (MASLD) in obesity, but the macronutrient carbon source for over half of hepatic fatty acid synthesis remains undetermined. Here, we discover that dietary protein, rather than carbohydrates or fat, is the primary nutritional risk factor for MASLD in humans. Consistently, ex vivo tracing studies identify amino acids as a major carbon supplier for the tricarboxylic acid (TCA) cycle and lipogenesis in isolated mouse hepatocytes. In vivo, dietary amino acids are twice as efficient as glucose in fueling hepatic fatty acid synthesis. The onset of obesity further drives amino acids into fatty acid synthesis through reductive carboxylation, while genetic and chemical interventions that divert amino acid carbon away from lipogenesis alleviate hepatic steatosis. Finally, low-protein diets (LPDs) not only prevent body weight gain in obese mice but also reduce hepatic lipid accumulation and liver damage. Together, this study uncovers the significant role of amino acids in hepatic lipogenesis and suggests a previously unappreciated nutritional intervention target for MASLD.
    Keywords:  DNL; MASH; MASLD; NAFLD; amino acids; dietary protein; glucose; glutamine; lipogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.001
  9. JCI Insight. 2024 Oct 29. pii: e185952. [Epub ahead of print]
    ASCL1 regulates and cooperates with FOXA2 to drive terminal neuroendocrine phenotype in prostate cancer.
    Shaghayegh Nouruzi, Takeshi Namekawa, Nakisa Tabrizian, Maxim Kobelev, Olena Sivak, Joshua M Scurll, Cassandra Jingjing Cui, Dwaipayan Ganguli, Amina Zoubeidi.
      Lineage plasticity mediates resistance to androgen receptor pathway inhibitors (ARPIs) and progression from adenocarcinoma to neuroendocrine prostate cancer (NEPC), a highly aggressive and poorly understood subtype. ASCL1 has emerged as a central regulator of the lineage plasticity driving neuroendocrine differentiation. Here, we showed that ASCL1 was reprogrammed in ARPI-induced transition to the terminal NEPC and identified that the ASCL1 binding pattern tailored the expression of lineage-determinant transcription factor combinations that underlying discrete terminal NEPC identity. Notably, we identified FOXA2 as a major co-factor of ASCL1 in terminal NEPC, which is highly expressed in ASCL1-driven NEPC. Mechanistically, FOXA2 and ASCL1 interacted and worked in concert to orchestrate terminal neuronal differentiation. We identified that Prospero-Related Homeobox 1 was a target of ASCL1 and FOXA2. Targeting prospero-related homeobox 1 abrogated neuroendocrine characteristics and led to a decrease in cell proliferation in vitro and tumor growth in vivo. Our findings provide insights into the molecular conduit underlying the interplay between different lineage-determinant transcription factors to support the neuroendocrine identity and nominate prospero-related homeobox 1 as a potential target in ASCL1 high NEPC.
    Keywords:  Cell biology; Epigenetics; Neuroendocrine regulation; Prostate cancer
    DOI:  https://doi.org/10.1172/jci.insight.185952
  10. J Biol Chem. 2024 Oct 28. pii: S0021-9258(24)02442-6. [Epub ahead of print] 107940
    The GPCR adaptor protein Norbin controls the trafficking of C5aR1 and CXCR4 in mouse neutrophils.
    Stephen A Chetwynd, Richard J Ward, Graeme Milligan, Heidi C E Welch.
      Norbin (Neurochondrin, NCDN) is a GPCR adaptor protein known for its importance in neuronal function. Norbin works by binding to numerous GPCRs, controlling their steady state trafficking and sometimes their agonist-induced internalisation, as well as their signalling. We recently showed that Norbin is expressed in neutrophils, limits the surface levels of the GPCRs C5aR1 and CXCR4 in neutrophils, and suppresses neutrophil-mediated innate immunity. Here, we identify C5aR1 and CXCR4 as direct Norbin interactors and used mice with myeloid-Norbin deficiency to investigate the role of Norbin in the trafficking of endogenous C5aR1 and CXCR4 in primary neutrophils by flow cytometry and cell fractionation. We show that Norbin mediates the agonist-induced internalisation of C5aR1 through a β-arrestin-dependent mechanism and limits the recycling of internalised C5aR1 and CXCR4 back to the cell surface. Norbin does not control the constitutive internalisation of C5aR1 and CXCR4, nor does it affect the agonist-induced internalisation of CXCR4. Norbin suppresses C5aR1 signalling in mouse neutrophils by limiting the C5a-stimulated membrane translocation of Tiam1, Vav, and PKCδ, and activation of Erk and p38 Mapk pathways, as well as Gαi-dependent ROS production. Our study demonstrates how Norbin suppresses C5aR1 and CXCR4 function in neutrophils and increases our understanding of the mechanisms through which Norbin regulates GPCR trafficking generally, by identifying its importance in β-arrestin recruitment, β-arrestin dependent agonist-induced receptor internalisation, and receptor recycling.
    Keywords:  C5aR1; CXCR4; G protein-coupled receptor (GPCR); GPCR trafficking; Ncdn; Neurochondrin; P-Rex1; agonist-induced internalisation; receptor desensitization; receptor endocytosis; receptor recycling; β-arrestin
    DOI:  https://doi.org/10.1016/j.jbc.2024.107940
  11. Cell Metab. 2024 Oct 19. pii: S1550-4131(24)00396-6. [Epub ahead of print]
    Metabolic regulation of the glioblastoma stem cell epitranscriptome by malate dehydrogenase 2.
    Deguan Lv, Deobrat Dixit, Andrea F Cruz, Leo J Y Kim, Likun Duan, Xin Xu, Qiulian Wu, Cuiqing Zhong, Chenfei Lu, Zachary C Gersey, Ryan C Gimple, Qi Xie, Kailin Yang, Xiaojing Liu, Xiaoguang Fang, Xujia Wu, Reilly L Kidwell, Xiuxing Wang, Shideng Bao, Housheng H He, Jason W Locasale, Sameer Agnihotri, Jeremy N Rich.
      Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate. Targeting MDH2 induced accumulation of alpha-ketoglutarate (αKG), a critical co-factor for dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5). Forced expression of MDH2 increased m6A levels and inhibited ALKBH5 activity, both rescued by αKG supplementation. Reciprocally, targeting MDH2 reduced global m6A levels with platelet-derived growth factor receptor-β (PDGFRβ) as a regulated transcript. Pharmacological inhibition of MDH2 in GSCs augmented efficacy of dasatinib, an orally bioavailable multi-kinase inhibitor, including PDGFRβ. Collectively, stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms.
    Keywords:  ALKBH5; MDH2; PDGFRβ; alpha-ketoglutarate; cancer stem cell; epitranscriptomics; glioblastoma; m6A; malate-aspartate shuttle; metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2024.09.014
  12. Sci Adv. 2024 Nov;10(44): eadp7725
    Membrane potential stimulates ADP import and ATP export by the mitochondrial ADP/ATP carrier due to its positively charged binding site.
    Vasiliki Mavridou, Martin S King, Andre Bazzone, Roger Springett, Edmund R S Kunji.
      The mitochondrial adenosine 5'-diphosphate (ADP)/adenosine 5'-triphosphate (ATP) carrier imports ADP into the mitochondrion and exports ATP to the cell. Here, we demonstrate that 3.3 positive charges are translocated with the negatively charged substrate in each transport step. They can be assigned to three positively charged residues of the central substrate-binding site and two asparagine/arginine pairs. In this way, the membrane potential stimulates not only the ATP4- export step, as a net -0.7 charge is transported, but also the ADP3- import step, as a net +0.3 charge is transported with the electric field. These positive charge movements also inhibit the import of ATP and export of ADP in the presence of a membrane potential, allowing these nucleotides to be maintained at high concentrations in the cytosol and mitochondrial matrix to drive the hydrolysis and synthesis of ATP, respectively. Thus, this is the mechanism by which the membrane potential drives adenine nucleotide exchange with high directional fluxes to fuel the cellular processes.
    DOI:  https://doi.org/10.1126/sciadv.adp7725
  13. Cell. 2024 Oct 25. pii: S0092-8674(24)01154-1. [Epub ahead of print]
    Ovarian cancer-derived IL-4 promotes immunotherapy resistance.
    Gurkan Mollaoglu, Alexander Tepper, Chiara Falcomatà, Hunter T Potak, Luisanna Pia, Angelo Amabile, Jaime Mateus-Tique, Noam Rabinovich, Matthew D Park, Nelson M LaMarche, Rachel Brody, Lindsay Browning, Jia-Ren Lin, Dmitriy Zamarin, Peter K Sorger, Sandro Santagata, Miriam Merad, Alessia Baccarini, Brian D Brown.
      Ovarian cancer is resistant to immunotherapy, and this is influenced by the immunosuppressed tumor microenvironment (TME) dominated by macrophages. Resistance is also affected by intratumoral heterogeneity, whose development is poorly understood. To identify regulators of ovarian cancer immunity, we employed a spatial functional genomics screen (Perturb-map), focused on receptor/ligands hypothesized to be involved in tumor-macrophage communication. Perturb-map recapitulated tumor heterogeneity and revealed that interleukin-4 (IL-4) promotes resistance to anti-PD-1. We find ovarian cancer cells are the key source of IL-4, which directs the formation of an immunosuppressive TME via macrophage control. IL-4 loss was not compensated by nearby IL-4-expressing clones, revealing short-range regulation of TME composition dictating tumor evolution. Our studies show heterogeneous TMEs can emerge from localized altered expression of cancer-derived cytokines/chemokines that establish immune-rich and immune-excluded neighborhoods, which drive clone selection and immunotherapy resistance. They also demonstrate the potential of targeting IL-4 signaling to enhance ovarian cancer response to immunotherapy.
    Keywords:  CCL7; IL-4; Perturb-map; immunotherapy; intratumoral heterogeneity; macrophages; multiplex imaging; ovarian cancer; spatial CRISPR screens; spatial genomics; tumor immunology; tumor microenvironment; tumor neighborhood; type 2 immunity
    DOI:  https://doi.org/10.1016/j.cell.2024.10.006
  14. Cell Death Dis. 2024 Oct 26. 15(10): 777
    Impaired activation of succinate-induced type 2 immunity and secretory cell production in the small intestines of Ptk6-/- male mice.
    Katarina Vlajic, Wenjun Bie, Milica B Gilic, Angela L Tyner.
      Protein tyrosine kinase 6 (PTK6) is an intracellular tyrosine kinase that is distantly related to the SRC family of tyrosine kinases. It is expressed in epithelial linings and regulates regeneration and repair of the intestinal epithelium. Analysis of publicly available datasets showed Ptk6 is upregulated in tuft cells upon activation of type 2 immunity. We found that disruption of Ptk6 influences gene expression involved in intestinal immune responses. Administration of succinate, which mimics infection and activates tuft cells, revealed PTK6-dependent activation of innate immune responses in male but not female mice. In contrast to all wild type and Ptk6-/- female mice, Ptk6-/- male mice do not activate innate immunity or upregulate differentiation of the tuft and goblet secretory cell lineages following succinate treatment. Mechanistically, we found that PTK6 regulates Il25 and Irag2, genes that are required for tuft cell effector functions and activation of type 2 innate immunity, in organoids derived from intestines of male but not female mice. In patients with Crohn's disease, PTK6 is upregulated in tuft cells in noninflamed regions of intestine. These data highlight roles for PTK6 in contributing to sex differences in intestinal innate immunity and provide new insights into the regulation of IL-25.
    DOI:  https://doi.org/10.1038/s41419-024-07149-9
  15. Sci Transl Med. 2024 Oct 30. 16(771): eadk1168
    Protumoral lipid droplet-loaded macrophages are enriched in human glioblastoma and can be therapeutically targeted.
    Valeria Governa, Kelin Gonçalves de Oliveira, Anna Bång-Rudenstam, Svenja Offer, Myriam Cerezo-Magaña, Jiaxin Li, Sarah Beyer, Maria C Johansson, Ann-Sofie Månsson, Charlotte Edvardsson, Faris Durmo, Emma Gustafsson, Axel Boukredine, Pauline Jeannot, Katja Schmidt, Emelie Gezelius, Julien A Menard, Raquel Garza, Johan Jakobsson, Therese de Neergaard, Pia C Sundgren, Aliisa M Tiihonen, Hannu Haapasalo, Kirsi J Rautajoki, Pontus Nordenfelt, Anna Darabi, Karin Forsberg-Nilsson, Alexander Pietras, Hugo Talbot, Johan Bengzon, Mattias Belting.
      Glioblastoma presents a formidable clinical challenge because of its complex microenvironment. Here, we characterized tumor-associated foam cells (TAFs), a type of lipid droplet-loaded macrophage, in human glioblastoma. Through extensive analyses of patient tumors, together with in vitro and in vivo investigations, we found that TAFs exhibit distinct protumorigenic characteristics related to hypoxia, mesenchymal transition, angiogenesis, and impaired phagocytosis, and their presence correlates with worse outcomes for patients with glioma. We further demonstrated that TAF formation is facilitated by lipid scavenging from extracellular vesicles released by glioblastoma cells. We found that targeting key enzymes involved in lipid droplet formation, such as diacylglycerol O-acyltransferase or long-chain acyl-CoA synthetase, effectively disrupted TAF functionality. Together, these data highlight TAFs as a prominent immune cell population in glioblastoma and provide insights into their contribution to the tumor microenvironment. Disrupting lipid droplet formation to target TAFs may represent an avenue for future therapeutic development for glioblastoma.
    DOI:  https://doi.org/10.1126/scitranslmed.adk1168
  16. Nat Commun. 2024 Oct 30. 15(1): 9388
    N-acetyltransferase 10 is implicated in the pathogenesis of cycling T cell-mediated autoimmune and inflammatory disorders in mice.
    Wen-Ping Li, Xin-Tao Mao, Jia-Huan Xie, Jie-Yu Li, Bao-Qin Liu, Le-Xi Wu, Bing Yang, Yi-Yuan Li, Jin Jin.
      T cell expansion has a crucial function in both autoimmune and chronic inflammatory diseases, with cycling T cells contributing to the pathogenesis of autoimmune diseases by causing uncontrolled immune responses and tissue damage. Yet the regulatory mechanisms governing T cell expansion remain incompletely understood. Here we show that the enzyme N-acetyltransferase 10 (NAT10) regulates T cell activation and proliferation upon antigen stimulation. T cell-specific NAT10 deficiency in mice reduces the number of mature T cells in peripheral lymphoid organs. Mechanistically, NAT10 acetylates RACK1 at K185, preventing subsequent RACK1 K48-linked ubiquitination and degradation. The increased RACK1 stability alters ribosome formation and cellular metabolism, leading to enhanced supply of energy and biosynthetic precursors and, eventually, T cell proliferation. Our findings thus highlight the essential function of NAT10 in T cell self-renewal and metabolism and elucidate NAT10 mode of action for the potential development of novel therapies for immune-related disorders.
    DOI:  https://doi.org/10.1038/s41467-024-53350-x
  17. Mol Cell. 2024 Oct 22. pii: S1097-2765(24)00825-6. [Epub ahead of print]
    Palmitoylation licenses RIPK1 kinase activity and cytotoxicity in the TNF pathway.
    Na Zhang, Jianping Liu, Rui Guo, Lingjie Yan, Yuanxin Yang, Chen Shi, Mengmeng Zhang, Bing Shan, Wanjin Li, Jinyang Gu, Daichao Xu.
      Tumor necrosis factor (TNF)-induced receptor-interacting serine/threonine protein kinase 1 (RIPK1)-mediated cell death, including apoptosis and necroptosis, is increasingly recognized as a major driver of inflammatory diseases. Cell death checkpoints normally suppress RIPK1 kinase to safeguard the organism from its detrimental consequences. However, the mechanisms licensing RIPK1 kinase activity when a protective checkpoint is disabled remain unclear. Here, we identified S-palmitoylation as a licensing modification for RIPK1 kinase. TNF induces RIPK1 palmitoylation, mediated by DHHC5 and dependent on K63-linked ubiquitination of RIPK1, which enhances RIPK1 kinase activity by promoting the homo-interaction of its kinase domain and promotes cell death upon cell death checkpoint blockade. Furthermore, DHHC5 is amplified by fatty acid in the livers of mice with metabolic dysfunction-associated steatohepatitis, contributing to increased RIPK1 cytotoxicity observed in this condition. Our findings reveal that ubiquitination-dependent palmitoylation licenses RIPK1 kinase activity to induce downstream cell death signaling and suggest RIPK1 palmitoylation as a feasible target for inflammatory diseases.
    Keywords:  DHHC5; RIPK1; TNF pathway; apoptosis; metabolic dysfunction-associated steatohepatitis; necroptosis; palmitoyl acyltransferase; palmitoylation
    DOI:  https://doi.org/10.1016/j.molcel.2024.10.002
  18. Sci Adv. 2024 Nov;10(44): eadn1849
    Metabolic programs drive function of therapeutic NK cells in hypoxic tumor environments.
    Philippa R Kennedy, Upasana Sunil Arvindam, Shee Kwan Phung, Brianna Ettestad, Xueyang Feng, Yunmin Li, Quinlan M Kile, Peter Hinderlie, Melissa Khaw, Rih-Sheng Huang, Marissa Kaufman, Patrycja Puchalska, Amanda Russell, Jonah Butler, Lucas Abbott, Paul McClure, Xianghua Luo, Quynhanh T Lu, Bruce R Blazar, Peter A Crawford, James Lim, Jeffrey S Miller, Martin Felices.
      Limited oxygen (hypoxia) in solid tumors poses a challenge to successful immunotherapy with natural killer (NK) cells. NK cells have impaired cytotoxicity when cultured in hypoxia (1% oxygen) but not physiologic (>5%) or atmospheric oxygen (20%). We found that changes to cytotoxicity were regulated at the transcriptional level and accompanied by metabolic dysregulation. Dosing with interleukin-15 (IL-15) enhanced NK cell cytotoxicity in hypoxia, but preactivation with feeder cells bearing IL-21 and 4-1BBL was even better. Preactivation resulted in less perturbed metabolism in hypoxia; greater resistance to oxidative stress; and no hypoxia-induced loss of transcription factors (T-bet and Eomes), activating receptors, adhesion molecules (CD2), and cytotoxic proteins (TRAIL and FasL). There remained a deficit in CD122/IL-2Rβ when exposed to hypoxia, which affected IL-15 signaling. However, tri-specific killer engager molecules that deliver IL-15 in the context of anti-CD16/FcγRIII were able to bypass this deficit, enhancing cytotoxicity of both fresh and preactivated NK cells in hypoxia.
    DOI:  https://doi.org/10.1126/sciadv.adn1849
  19. Nat Metab. 2024 Oct 29.
    Branched-chain α-ketoacids aerobically activate HIF1α signalling in vascular cells.
    Wusheng Xiao, Nishith Shrimali, Niv Vigder, William M Oldham, Clary B Clish, Huamei He, Samantha J Wong, Bradley M Wertheim, Elena Arons, Marcia C Haigis, Jane A Leopold, Joseph Loscalzo.
      Hypoxia-inducible factor 1α (HIF1α) is a master regulator of biological processes in hypoxia. Yet, the mechanisms and biological consequences of aerobic HIF1α activation by intrinsic factors, particularly in normal (primary) cells, remain elusive. Here we show that HIF1α signalling is activated in several human primary vascular cells in normoxia and in vascular smooth muscle cells of normal human lungs. Mechanistically, aerobic HIF1α activation is mediated by paracrine secretion of three branched-chain α-ketoacids (BCKAs), which suppress PHD2 activity via direct inhibition and via LDHA-mediated generation of L-2-hydroxyglutarate. BCKA-mediated HIF1α signalling activation stimulated glycolytic activity and governed a phenotypic switch of pulmonary artery smooth muscle cells, which correlated with BCKA metabolic dysregulation and pathophenotypic changes in pulmonary arterial hypertension patients and male rat models. We thus identify BCKAs as previously unrecognized signalling metabolites that aerobically activate HIF1α and that the BCKA-HIF1α pathway modulates vascular smooth muscle cell function, an effect that may be relevant to pulmonary vascular pathobiology.
    DOI:  https://doi.org/10.1038/s42255-024-01150-4
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