bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2022‒04‒17
25 papers selected by
Ralitsa Radostinova Madsen
University College London Cancer Institute
  1. Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer.
  2. Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.
  3. SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies.
  4. An update on genetically encoded lipid biosensors.
  5. Elimination of Vitamin D Signaling Causes Increased Mortality in a Model of Overactivation of the Insulin Receptor: Role of Lipid Metabolism.
  6. Data-driven learning how oncogenic gene expression locally alters heterocellular networks.
  7. TMT-Based Multiplexed Quantitation of N-Glycopeptides Reveals Glycoproteome Remodeling Induced by Oncogenic Mutations.
  8. Somatic mutation rates scale with lifespan across mammals.
  9. Metabolic Reprogramming of Alloreactive T Cells Through TCR/MYC/mTORC1/E2F6 Signaling in aGvHD Patients.
  10. Automated, high-dimensional evaluation of physiological aging and resilience in outbred mice.
  11. Mutational clocks tick differently across species.
  12. PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma.
  13. Lyso-PAF, a biologically inactive phospholipid, contributes to RAF1 activation.
  14. Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.
  15. The hepatocyte insulin receptor is required to program the liver clock and rhythmic gene expression.
  16. A feedback loop engaging propionate catabolism intermediates controls mitochondrial morphology.
  17. Extracellular ATP facilitates cell extrusion from epithelial layers mediated by cell competition or apoptosis.
  18. Chemical reprogramming of human somatic cells to pluripotent stem cells.
  19. The HOPS tethering complex is required to maintain signaling endosome identity and TORC1 activity.
  20. Navigating EMT with COMPASS and PRC2.
  21. Vinculin controls endothelial cell junction dynamics during vascular lumen formation.
  22. Ligand-receptor promiscuity enables cellular addressing.
  23. Evaluating human genetic support for hypothesized metabolic disease genes.
  24. Mitochondria and the future of RASopathies: the emergence of bioenergetics.
  25. Sphingolipids control dermal fibroblast heterogeneity.
  1. Nat Commun. 2022 Apr 13. 13(1): 1974
    Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer.
    Yujun Hao, Baoyu He, Liping Wu, Yamu Li, Chao Wang, Ting Wang, Longci Sun, Yanhua Zhang, Yangyang Zhan, Yiqing Zhao, Sanford Markowitz, Martina Veigl, Ronald A Conlon, Zhenghe Wang.
      PI3Ks consist of p110 catalytic subunits and p85 regulatory subunits. PIK3CA, encoding p110α, is frequently mutated in human cancers. Most PIK3CA mutations are clustered in the helical domain or the kinase domain. Here, we report that p85β disassociates from p110α helical domain mutant protein and translocates into the nucleus through a nuclear localization sequence (NLS). Nuclear p85β recruits deubiquitinase USP7 to stabilize EZH1 and EZH2 and enhances H3K27 trimethylation. Knockout of p85β or p85β NLS mutant reduces the growth of tumors harboring a PIK3CA helical domain mutation. Our studies illuminate a novel mechanism by which PIK3CA helical domain mutations exert their oncogenic function. Finally, a combination of Alpelisib, a p110α-specific inhibitor, and an EZH inhibitor, Tazemetostat, induces regression of xenograft tumors harboring a PIK3CA helical domain mutation, but not tumors with either a WT PIK3CA or a PIK3CA kinase domain mutation, suggesting that the drug combination could be an effective therapeutic approach for PIK3CA helical domain mutant tumors.
    DOI:  https://doi.org/10.1038/s41467-022-29585-x
  2. Science. 2022 Apr 15. 376(6590): eabf8271
    Inhibition of nonalcoholic fatty liver disease in mice by selective inhibition of mTORC1.
    Bridget S Gosis, Shogo Wada, Chelsea Thorsheim, Kristina Li, Sunhee Jung, Joshua H Rhoades, Yifan Yang, Jeffrey Brandimarto, Li Li, Kahealani Uehara, Cholsoon Jang, Matthew Lanza, Nathan B Sanford, Marc R Bornstein, Sunhye Jeong, Paul M Titchenell, Sudha B Biddinger, Zoltan Arany.
      Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) remain without effective therapies. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is a potential therapeutic target, but conflicting interpretations have been proposed for how mTORC1 controls lipid homeostasis. We show that selective inhibition of mTORC1 signaling in mice, through deletion of the RagC/D guanosine triphosphatase-activating protein folliculin (FLCN), promotes activation of transcription factor E3 (TFE3) in the liver without affecting other mTORC1 targets and protects against NAFLD and NASH. Disease protection is mediated by TFE3, which both induces lipid consumption and suppresses anabolic lipogenesis. TFE3 inhibits lipogenesis by suppressing proteolytic processing and activation of sterol regulatory element-binding protein-1c (SREBP-1c) and by interacting with SREBP-1c on chromatin. Our data reconcile previously conflicting studies and identify selective inhibition of mTORC1 as a potential approach to treat NASH and NAFLD.
    DOI:  https://doi.org/10.1126/science.abf8271
  3. Cell Signal. 2022 Apr 07. pii: S0898-6568(22)00092-4. [Epub ahead of print]94 110331
    SYK and ZAP70 kinases in autoimmunity and lymphoid malignancies.
    Etienne Leveille, Lai N Chan, Abu-Sayeef Mirza, Kohei Kume, Markus Müschen.
      SYK and ZAP70 nonreceptor tyrosine kinases serve essential roles in initiating B-cell receptor (BCR) and T-cell receptor (TCR) signaling in B- and T-lymphocytes, respectively. Despite their structural and functional similarity, expression of SYK and ZAP70 is strictly separated during B- and T-lymphocyte development, the reason for which was not known. Aberrant co-expression of ZAP70 with SYK was first identified in B-cell chronic lymphocytic leukemia (CLL) and is considered a biomarker of aggressive disease and poor clinical outcomes. We recently found that aberrant ZAP70 co-expression not only functions as an oncogenic driver in CLL but also in various other B-cell malignancies, including acute lymphoblastic leukemia (B-ALL) and mantle cell lymphoma. Thereby, aberrantly expressed ZAP70 redirects SYK and BCR-downstream signaling from NFAT towards activation of the PI3K-pathway. In the sole presence of SYK, pathological BCR-signaling in autoreactive or premalignant cells induces NFAT-activation and NFAT-dependent anergy and negative selection. In contrast, negative selection of pathological B-cells is subverted when ZAP70 diverts SYK from activation of NFAT towards tonic PI3K-signaling, which promotes survival instead of cell death. We discuss here how both B-cell malignancies and autoimmune diseases frequently evolve to harness this mechanism, highlighting the importance of developmental separation of the two kinases as an essential safeguard.
    Keywords:  Antigen receptor signaling; B-cell malignancies; Negative selection; SYK; ZAP70
    DOI:  https://doi.org/10.1016/j.cellsig.2022.110331
  4. Mol Biol Cell. 2022 May 01. 33(5): tp2
    An update on genetically encoded lipid biosensors.
    Gerald R V Hammond, Morgan M C Ricci, Claire C Weckerly, Rachel C Wills.
      Specific lipid species play central roles in cell biology. Their presence or enrichment in individual membranes can control properties or direct protein localization and/or activity. Therefore, probes to detect and observe these lipids in intact cells are essential tools in the cell biologist's freezer box. Herein, we discuss genetically encoded lipid biosensors, which can be expressed as fluorescent protein fusions to track lipids in living cells. We provide a state-of-the-art list of the most widely available and reliable biosensors and highlight new probes (circa 2018-2021). Notably, we focus on advances in biosensors for phosphatidylinositol, phosphatidic acid, and PI 3-kinase lipid products.
    DOI:  https://doi.org/10.1091/mbc.E21-07-0363
  5. Nutrients. 2022 Apr 05. pii: 1516. [Epub ahead of print]14(7):
    Elimination of Vitamin D Signaling Causes Increased Mortality in a Model of Overactivation of the Insulin Receptor: Role of Lipid Metabolism.
    Maria Crespo-Masip, Aurora Perez-Gomez, Alicia Garcia-Carrasco, Ramiro Jover, Carla Guzmán, Xavier Dolcet, Mercé Ibarz, Cristina Martínez, Àuria Eritja, Juan Miguel Diaz-Tocados, José Manuel Valdivielso.
      Vitamin D (VD) deficiency has been associated with cancer and diabetes. Insulin signaling through the insulin receptor (IR) stimulates cellular responses by activating the PI3K/AKT pathway. PTEN is a tumor suppressor and a negative regulator of the pathway. Its absence enhances insulin signaling leading to hypoglycemia, a dangerous complication found after insulin overdose. We analyzed the effect of VD signaling in a model of overactivation of the IR. We generated inducible double KO (DKO) mice for the VD receptor (VDR) and PTEN. DKO mice showed severe hypoglycemia, lower total cholesterol and increased mortality. No macroscopic tumors were detected. Analysis of the glucose metabolism did not show clear differences that would explain the increased mortality. Glucose supplementation, either systemically or directly into the brain, did not enhance DKO survival. Lipidic liver metabolism was altered as there was a delay in the activation of genes related to β-oxidation and a decrease in lipogenesis in DKO mice. High-fat diet administration in DKO significantly improved its life span. Lack of vitamin D signaling increases mortality in a model of overactivation of the IR by impairing lipid metabolism. Clinically, these results reveal the importance of adequate Vitamin D levels in T1D patients.
    Keywords:  diabetes; fatty acids; hypoglycemia; insulin overdose; lipolysis
    DOI:  https://doi.org/10.3390/nu14071516
  6. Nat Commun. 2022 Apr 13. 13(1): 1986
    Data-driven learning how oncogenic gene expression locally alters heterocellular networks.
    David J Klinke Ii, Audry Fernandez, Wentao Deng, Atefeh Razazan, Habibolla Latifizadeh, Anika C Pirkey.
      Developing drugs increasingly relies on mechanistic modeling and simulation. Models that capture causal relations among genetic drivers of oncogenesis, functional plasticity, and host immunity complement wet experiments. Unfortunately, formulating such mechanistic cell-level models currently relies on hand curation, which can bias how data is interpreted or the priority of drug targets. In modeling molecular-level networks, rules and algorithms are employed to limit a priori biases in formulating mechanistic models. Here we combine digital cytometry with Bayesian network inference to generate causal models of cell-level networks linking an increase in gene expression associated with oncogenesis with alterations in stromal and immune cell subsets from bulk transcriptomic datasets. We predict how increased Cell Communication Network factor 4, a secreted matricellular protein, alters the tumor microenvironment using data from patients diagnosed with breast cancer and melanoma. Predictions are then tested using two immunocompetent mouse models for melanoma, which provide consistent experimental results.
    DOI:  https://doi.org/10.1038/s41467-022-29636-3
  7. ACS Omega. 2022 Apr 05. 7(13): 11023-11032
    TMT-Based Multiplexed Quantitation of N-Glycopeptides Reveals Glycoproteome Remodeling Induced by Oncogenic Mutations.
    Mayank Saraswat, Kiran Kumar Mangalaparthi, Kishore Garapati, Akhilesh Pandey.
      Glycoproteomics, or the simultaneous characterization of glycans and their attached peptides, is increasingly being employed to generate catalogs of glycopeptides on a large scale. Nevertheless, quantitative glycoproteomics remains challenging even though isobaric tagging reagents such as tandem mass tags (TMT) are routinely used for quantitative proteomics. Here, we present a workflow that combines the enrichment or fractionation of TMT-labeled glycopeptides with size-exclusion chromatography (SEC) for an in-depth and quantitative analysis of the glycoproteome. We applied this workflow to study the cellular glycoproteome of an isogenic mammary epithelial cell system that recapitulated oncogenic mutations in the PIK3CA gene, which codes for the phosphatidylinositol-3-kinase catalytic subunit. As compared to the parental cells, cells with mutations in exon 9 (E545K) or exon 20 (H1047R) of the PIK3CA gene exhibited site-specific glycosylation alterations in 464 of the 1999 glycopeptides quantified. Our strategy led to the discovery of site-specific glycosylation changes in PIK3CA mutant cells in several important receptors, including cell adhesion proteins such as integrin β-6 and CD166. This study demonstrates that the SEC-based enrichment of glycopeptides is a simple and robust method with minimal sample processing that can easily be coupled with TMT-labeling for the global quantitation of glycopeptides.
    DOI:  https://doi.org/10.1021/acsomega.1c06970
  8. Nature. 2022 Apr 13.
    Somatic mutation rates scale with lifespan across mammals.
    Alex Cagan, Adrian Baez-Ortega, Natalia Brzozowska, Federico Abascal, Tim H H Coorens, Mathijs A Sanders, Andrew R J Lawson, Luke M R Harvey, Shriram Bhosle, David Jones, Raul E Alcantara, Timothy M Butler, Yvette Hooks, Kirsty Roberts, Elizabeth Anderson, Sharna Lunn, Edmund Flach, Simon Spiro, Inez Januszczak, Ethan Wrigglesworth, Hannah Jenkins, Tilly Dallas, Nic Masters, Matthew W Perkins, Robert Deaville, Megan Druce, Ruzhica Bogeska, Michael D Milsom, Björn Neumann, Frank Gorman, Fernando Constantino-Casas, Laura Peachey, Diana Bochynska, Ewan St John Smith, Moritz Gerstung, Peter J Campbell, Elizabeth P Murchison, Michael R Stratton, Iñigo Martincorena.
      The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans1-7. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans8, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.
    DOI:  https://doi.org/10.1038/s41586-022-04618-z
  9. Front Immunol. 2022 ;13 850177
    Metabolic Reprogramming of Alloreactive T Cells Through TCR/MYC/mTORC1/E2F6 Signaling in aGvHD Patients.
    Zengkai Pan, Aijie Huang, Yang He, Zilu Zhang, Chuanhe Jiang, Luxiang Wang, Kai Qing, Sujiang Zhang, Jianmin Wang, Xiaoxia Hu.
      Acute graft-versus-host disease (aGvHD) is the most common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and significantly linked with morbidity and mortality. Although much work has been engaged to investigate aGvHD pathogenesis, the understanding of alloreactive T-cell activation remains incomplete. To address this, we studied transcriptional activation of carbohydrate, nucleotide, tricarboxylic acid (TCA) cycle, and amino acid metabolism of T cells before aGvHD onset by mining the Gene Expression Omnibus (GEO) datasets. Glycolysis had the most extensive correlation with other activated metabolic sub-pathways. Through Pearson correlation analyses, we found that glycolytic activation was positively correlated with activated CD4 memory T-cell subset and T-cell proliferation and migration. T-cell receptor (TCR), mechanistic target of rapamycin complex 1 (mTORC1), myelocytomatosis oncogene (MYC) signaling pathways and E2F6 might be "master regulators" of glycolytic activity. aGvHD predictive model constructed by glycolytic genes (PFKP, ENO3, and GAPDH) through logistic regression showed high predictive and discriminative value. Furthermore, higher expressions of PFKP, ENO3, and GAPDH in alloreactive T cells were confirmed in our pre-aGvHD patient cohort. And the predictive value of the aGvHD risk model was also validated. In summary, our study demonstrated that glycolytic activation might play a pivotal function in alloreactive T-cell activation before aGvHD onset and would be the potential target for aGvHD therapy.
    Keywords:  T cells; aGvHD; allogeneic hematopoietic stem cell transplantation; glycolytic; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2022.850177
  10. Elife. 2022 Apr 11. pii: e72664. [Epub ahead of print]11
    Automated, high-dimensional evaluation of physiological aging and resilience in outbred mice.
    Zhenghao Chen, Anil Raj, G V Prateek, Andrea Di Francesco, Justin Liu, Brice E Keyes, Ganesh Kolumam, Vladimir Jojic, Adam Freund.
      Behavior and physiology are essential readouts in many studies but have not benefited from the high-dimensional data revolution that has transformed molecular and cellular phenotyping. To address this, we developed an approach that combines commercially available automated phenotyping hardware with a systems biology analysis pipeline to generate a high-dimensional readout of mouse behavior/physiology, as well as intuitive and health-relevant summary statistics (resilience and biological age). We used this platform to longitudinally evaluate aging in hundreds of outbred mice across an age range from 3 months to 3.4 years. In contrast to the assumption that aging can only be measured at the limits of animal ability via challenge-based tasks, we observed widespread physiological and behavioral aging starting in early life. Using network connectivity analysis, we found that organism-level resilience exhibited an accelerating decline with age that was distinct from the trajectory of individual phenotypes. We developed a method, Combined Aging and Survival Prediction of Aging Rate (CASPAR), for jointly predicting chronological age and survival time and showed that the resulting model is able to predict both variables simultaneously, a behavior that is not captured by separate age and mortality prediction models. This study provides a uniquely high-resolution view of physiological aging in mice and demonstrates that systems-level analysis of physiology provides insights not captured by individual phenotypes. The approach described here allows aging, and other processes that affect behavior and physiology, to be studied with improved throughput, resolution, and phenotypic scope.
    Keywords:  aging; computational biology; healthspan; mouse; physiology; resilience; systems biology
    DOI:  https://doi.org/10.7554/eLife.72664
  11. Nature. 2022 Apr;604(7906): 435-436
    Mutational clocks tick differently across species.
    Alexander N Gorelick, Kamila Naxerova.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-022-00976-w
  12. Am J Cancer Res. 2022 ;12(3): 1102-1115
    PIK-75 overcomes venetoclax resistance via blocking PI3K-AKT signaling and MCL-1 expression in mantle cell lymphoma.
    Shengjian Huang, Yang Liu, Zhihong Chen, Michael Wang, Vivian C Jiang.
      Therapeutic resistance is the major challenge in clinic for patients with mantle cell lymphoma (MCL), an aggressive subtype of B-cell lymphoma. In addition to the FDA-approved Bruton's tyrosine kinase (BTK) inhibitors, multiple clinical trials have demonstrated clinical benefits in targeting BCL-2 by venetoclax and reported to greatly improve clinical outcome for refractory/relapsed patients with MCL alone or in combination with BTK inhibitors. However, resistance to venetoclax is no exception and marks as a new clinic challenge. To decode the underlying mechanisms driving venetoclax resistance, we established two MCL cell lines, Mino-Re and Rec1-Re, with acquired resistance to venetoclax from sensitive Mino and Rec-1. Using reverse phase protein assay (RPPA), an agnostic proteomic approach, we identified targetable signaling pathways that are associated with acquired venetoclax resistance in Mino-Re and Rec1-Re cells. A panel of pro-survival signals was identified to correlate well with venetoclax-resistance, including increased expression of MCL-1, BCL-xL and AKT phosphorylation, and decreased expression of BIM, BAX and PTEN. Based on a high throughput drug screening of over 320 FDA-approved/investigational drugs in the paired venetoclax-sensitive and -resistant cell lines Mino-Re and Rec1-Re, we identified the top candidates that are capable to overcome acquired venetoclax resistance in these cells. The best candidate is PIK-75, a dual inhibitor targeting both PI3K and CDK9. Its action to overcome venetoclax resistance was further confirmed in additional cell lines with primary venetoclax resistance (n=4) and primary patient samples (n=21). Mechanistically, PIK75 treatment potently diminished the elevated MCL-1 expression and AKT activation in cells with acquired or primary venetoclax resistance and resulted in potent anti-MCL activity to overcome these resistances. In addition, PIK75 is also potent in overcoming tumor microenvironment (TME)-associated venetoclax resistance. Furthermore, PIK-75 treatment is efficacious in overcoming primary and acquired venetoclax resistance in xenograft models and inhibited tumor cell dissemination to spleen in mice. Altogether, our data demonstrated that PIK-75 is highly potent in overcoming primary, acquired, or stromal cells-induced venetoclax resistances in MCL cells and revealed a new tumor vulnerability that can be exploited clinically in difficult to treat MCL cases, especially those with venetoclax resistance.
    Keywords:  AKT; MCL-1; PI3K; PIK75; mantle cell lymphoma; venetoclax resistance
  13. Mol Cell. 2022 Apr 07. pii: S1097-2765(22)00264-7. [Epub ahead of print]
    Lyso-PAF, a biologically inactive phospholipid, contributes to RAF1 activation.
    Xue Gao, Yijie Liu, Yuancheng Li, Hao Fan, Rong Wu, Rukang Zhang, Brandon Faubert, Yu-Ying He, Marc B Bissonnette, Siyuan Xia, Dong Chen, Hui Mao, Titus J Boggon, Jing Chen.
      Phospholipase A2, group VII (PLA2G7) is widely recognized as a secreted, lipoprotein-associated PLA2 in plasma that converts phospholipid platelet-activating factor (PAF) to a biologically inactive product Lyso-PAF during inflammatory response. We report that intracellular PLA2G7 is selectively important for cell proliferation and tumor growth potential of melanoma cells expressing mutant NRAS, but not cells expressing BRAF V600E. Mechanistically, PLA2G7 signals through its product Lyso-PAF to contribute to RAF1 activation by mutant NRAS, which is bypassed by BRAF V600E. Intracellular Lyso-PAF promotes p21-activated kinase 2 (PAK2) activation by binding to its catalytic domain and altering ATP kinetics, while PAK2 significantly contributes to S338-phosphorylation of RAF1 in addition to PAK1. Furthermore, the PLA2G7-PAK2 axis is also required for full activation of RAF1 in cells stimulated by epidermal growth factor (EGF) or cancer cells expressing mutant KRAS. Thus, PLA2G7 and Lyso-PAF exhibit intracellular signaling functions as key elements of RAS-RAF1 signaling.
    Keywords:  BRAF-V600E; ERK; Lyso-PAF; MEK; RAF1; RAS; p21-activated kinase 2 (PAK2); phospholipase A2 group VII (PLA2G7); phospholipases A2 (PLA2s); platelet-activating factor (PAF)
    DOI:  https://doi.org/10.1016/j.molcel.2022.03.026
  14. iScience. 2022 Apr 15. 25(4): 104125
    Calcineurin/NFATc2 and PI3K/AKT signaling maintains β-cell identity and function during metabolic and inflammatory stress.
    Carly M Darden, Srividya Vasu, Jordan Mattke, Yang Liu, Christopher J Rhodes, Bashoo Naziruddin, Michael C Lawrence.
      Pancreatic islets respond to metabolic and inflammatory stress by producing hormones and other factors that induce adaptive cellular and systemic responses. Here we show that intracellular Ca2+ ([Ca2+]i) and ROS signals generated by high glucose and cytokine-induced ER stress activate calcineurin (CN)/NFATc2 and PI3K/AKT to maintain β-cell identity and function. This was attributed in part by direct induction of the endocrine differentiation gene RFX6 and suppression of several β-cell "disallowed" genes, including MCT1. CN/NFATc2 targeted p300 and HDAC1 to RFX6 and MCT1 promoters to induce and suppress gene transcription, respectively. In contrast, prolonged exposure to stress, hyperstimulated [Ca2+]i, or perturbation of CN/NFATc2 resulted in downregulation of RFX6 and induction of MCT1. These findings reveal that CN/NFATc2 and PI3K/AKT maintain β-cell function during acute stress, but β-cells dedifferentiate to a dysfunctional state upon loss or exhaustion of Ca2+/CN/NFATc2 signaling. They further demonstrate the utility of targeting CN/NFATc2 to restore β-cell function.
    Keywords:  Cell biology; Diabetology; Endocrinology; Molecular biology; Molecular interaction
    DOI:  https://doi.org/10.1016/j.isci.2022.104125
  15. Cell Rep. 2022 Apr 12. pii: S2211-1247(22)00426-0. [Epub ahead of print]39(2): 110674
    The hepatocyte insulin receptor is required to program the liver clock and rhythmic gene expression.
    Tiffany Fougeray, Arnaud Polizzi, Marion Régnier, Anne Fougerat, Sandrine Ellero-Simatos, Yannick Lippi, Sarra Smati, Frédéric Lasserre, Blandine Tramunt, Marine Huillet, Léonie Dopavogui, Juliette Salvi, Emmanuelle Nédélec, Vincent Gigot, Lorraine Smith, Claire Naylies, Caroline Sommer, Joel T Haas, Walter Wahli, Hélène Duez, Pierre Gourdy, Laurence Gamet-Payrastre, Alexandre Benani, Anne-Françoise Burnol, Nicolas Loiseau, Catherine Postic, Alexandra Montagner, Hervé Guillou.
      Liver physiology is circadian and sensitive to feeding and insulin. Food intake regulates insulin secretion and is a dominant signal for the liver clock. However, how much insulin contributes to the effect of feeding on the liver clock and rhythmic gene expression remains to be investigated. Insulin action partly depends on changes in insulin receptor (IR)-dependent gene expression. Here, we use hepatocyte-restricted gene deletion of IR to evaluate its role in the regulation and oscillation of gene expression as well as in the programming of the circadian clock in the adult mouse liver. We find that, in the absence of IR, the rhythmicity of core-clock gene expression is altered in response to day-restricted feeding. This change in core-clock gene expression is associated with defective reprogramming of liver gene expression. Our data show that an intact hepatocyte insulin receptor is required to program the liver clock and associated rhythmic gene expression.
    Keywords:  CLOCK; CP: Metabolism; CP: Molecular biology; circadian; hepatocyte; insulin; insulin receptor; liver; metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2022.110674
  16. Nat Cell Biol. 2022 Apr 13.
    A feedback loop engaging propionate catabolism intermediates controls mitochondrial morphology.
    Junxiang Zhou, Mei Duan, Xin Wang, Fengxia Zhang, Hejiang Zhou, Tengfei Ma, Qiuyuan Yin, Jie Zhang, Fei Tian, Guodong Wang, Chonglin Yang.
      D-2-Hydroxyglutarate (D-2HG) is an α-ketoglutarate-derived mitochondrial metabolite that causes D-2-hydroxyglutaric aciduria, a devastating developmental disorder. How D-2HG adversely affects mitochondria is largely unknown. Here, we report that in Caenorhabditis elegans, loss of the D-2HG dehydrogenase DHGD-1 causes D-2HG accumulation and mitochondrial damage. The excess D-2HG leads to a build-up of 3-hydroxypropionate (3-HP), a toxic metabolite in mitochondrial propionate oxidation, by inhibiting the 3-HP dehydrogenase HPHD-1. We demonstrate that 3-HP binds the MICOS subunit MIC60 (encoded by immt-1) and inhibits its membrane-binding and membrane-shaping activities. We further reveal that dietary and gut bacteria affect mitochondrial health by modulating the host production of 3-HP. These findings identify a feedback loop that links the toxic effects of D-2HG and 3-HP on mitochondria, thus providing important mechanistic insights into human diseases related to D-2HG and 3-HP.
    DOI:  https://doi.org/10.1038/s41556-022-00883-2
  17. Curr Biol. 2022 Apr 08. pii: S0960-9822(22)00491-2. [Epub ahead of print]
    Extracellular ATP facilitates cell extrusion from epithelial layers mediated by cell competition or apoptosis.
    Yusuke Mori, Naoka Shiratsuchi, Nanami Sato, Azusa Chaya, Nobuyuki Tanimura, Susumu Ishikawa, Mugihiko Kato, Ikumi Kameda, Shunsuke Kon, Yukinari Haraoka, Tohru Ishitani, Yasuyuki Fujita.
      For the maintenance of epithelial homeostasis, various aberrant or dysfunctional cells are actively eliminated from epithelial layers. This cell extrusion process mainly falls into two modes: cell-competition-mediated extrusion and apoptotic extrusion. However, it is not clearly understood whether and how these processes are governed by common molecular mechanisms. In this study, we demonstrate that the reactive oxygen species (ROS) levels are elevated within a wide range of epithelial layers around extruding transformed or apoptotic cells. The downregulation of ROS suppresses the extrusion process. Furthermore, ATP is extracellularly secreted from extruding cells, which promotes the ROS level and cell extrusion. Moreover, the extracellular ATP and ROS pathways positively regulate the polarized movements of surrounding cells toward extruding cells in both cell-competition-mediated and apoptotic extrusion. Hence, extracellular ATP acts as an "extrude me" signal and plays a prevalent role in cell extrusion, thereby sustaining epithelial homeostasis and preventing pathological conditions or disorders.
    Keywords:  ROS; RasV12; Scribble; apoptosis; cell competition; cell extrusion; cell migration; epithelia; extracellular ATP; mouse intestine
    DOI:  https://doi.org/10.1016/j.cub.2022.03.057
  18. Nature. 2022 Apr 13.
    Chemical reprogramming of human somatic cells to pluripotent stem cells.
    Jingyang Guan, Guan Wang, Jinlin Wang, Zhengyuan Zhang, Yao Fu, Lin Cheng, Gaofan Meng, Yulin Lyu, Jialiang Zhu, Yanqin Li, Yanglu Wang, Shijia Liuyang, Bei Liu, Zirun Yang, Huanjing He, Xinxing Zhong, Qijing Chen, Xu Zhang, Shicheng Sun, Weifeng Lai, Yan Shi, Lulu Liu, Lipeng Wang, Cheng Li, Shichun Lu, Hongkui Deng.
      Cellular reprogramming can manipulate the identity of cells to generate the desired cell types1-3. The use of cell intrinsic components, including oocyte cytoplasm and transcription factors, can enforce somatic cell reprogramming to pluripotent stem cells4-7. By contrast, chemical stimulation by exposure to small molecules offers an alternative approach that can manipulate cell fate in a simple and highly controllable manner8-10. However, human somatic cells are refractory to chemical stimulation owing to their stable epigenome2,11,12 and reduced plasticity13,14; it is therefore challenging to induce human pluripotent stem cells by chemical reprogramming. Here we demonstrate, by creating an intermediate plastic state, the chemical reprogramming of human somatic cells to human chemically induced pluripotent stem cells that exhibit key features of embryonic stem cells. The whole chemical reprogramming trajectory analysis delineated the induction of the intermediate plastic state at the early stage, during which chemical-induced dedifferentiation occurred, and this process was similar to the dedifferentiation process that occurs in axolotl limb regeneration. Moreover, we identified the JNK pathway as a major barrier to chemical reprogramming, the inhibition of which was indispensable for inducing cell plasticity and a regeneration-like program by suppressing pro-inflammatory pathways. Our chemical approach provides a platform for the generation and application of human pluripotent stem cells in biomedicine. This study lays foundations for developing regenerative therapeutic strategies that use well-defined chemicals to change cell fates in humans.
    DOI:  https://doi.org/10.1038/s41586-022-04593-5
  19. J Cell Biol. 2022 May 02. pii: e202109084. [Epub ahead of print]221(5):
    The HOPS tethering complex is required to maintain signaling endosome identity and TORC1 activity.
    Jieqiong Gao, Raffaele Nicastro, Marie-Pierre Péli-Gulli, Sophie Grziwa, Zilei Chen, Rainer Kurre, Jacob Piehler, Claudio De Virgilio, Florian Fröhlich, Christian Ungermann.
      The endomembrane system of eukaryotic cells is essential for cellular homeostasis during growth and proliferation. Previous work showed that a central regulator of growth, namely the target of rapamycin complex 1 (TORC1), binds both membranes of vacuoles and signaling endosomes (SEs) that are distinct from multivesicular bodies (MVBs). Interestingly, the endosomal TORC1, which binds membranes in part via the EGO complex, critically defines vacuole integrity. Here, we demonstrate that SEs form at a branch point of the biosynthetic and endocytic pathways toward the vacuole and depend on MVB biogenesis. Importantly, function of the HOPS tethering complex is essential to maintain the identity of SEs and proper endosomal and vacuolar TORC1 activities. In HOPS mutants, the EGO complex redistributed to the Golgi, which resulted in a partial mislocalization of TORC1. Our study uncovers that SE function requires a functional HOPS complex and MVBs, suggesting a tight link between trafficking and signaling along the endolysosomal pathway.
    DOI:  https://doi.org/10.1083/jcb.202109084
  20. Nat Cell Biol. 2022 Apr 11.
    Navigating EMT with COMPASS and PRC2.
    Evangelia Koutelou, Sharon Y R Dent.
      
    DOI:  https://doi.org/10.1038/s41556-022-00876-1
  21. Cell Rep. 2022 Apr 12. pii: S2211-1247(22)00410-7. [Epub ahead of print]39(2): 110658
    Vinculin controls endothelial cell junction dynamics during vascular lumen formation.
    Maria P Kotini, Miesje M van der Stoel, Jianmin Yin, Mitchell K Han, Bettina Kirchmaier, Johan de Rooij, Markus Affolter, Stephan Huveneers, Heinz-Georg Belting.
      Blood vessel morphogenesis is driven by coordinated endothelial cell behaviors. Active remodeling of cell-cell junctions promotes cellular plasticity while preserving vascular integrity. Here, we analyze the dynamics of endothelial adherens junctions during lumen formation in angiogenic sprouts in vivo. Live imaging in zebrafish reveals that lumen expansion is accompanied by the formation of transient finger-shaped junctions. Junctional fingers are positively regulated by blood pressure, whereas flow inhibition prevents their formation. Using fluorescent reporters, we show that junctional fingers contain the mechanotransduction protein vinculin. Furthermore, genetic deletion of vinculin prevents finger formation, a junctional defect that could be rescued by transient endothelial expression of vinculin. Our findings suggest a mechanism whereby lumen expansion leads to an increase in junctional tension, triggering recruitment of vinculin and formation of junctional fingers. We propose that endothelial cells employ force-dependent junctional remodeling to counteract external forces in order to maintain vascular integrity during sprouting angiogenesis.
    Keywords:  CP: Cell biology; VE-cadherin; angiogenesis; cell-cell adhesion; junctional dynamics; lumenization; vinculin; zebrafish
    DOI:  https://doi.org/10.1016/j.celrep.2022.110658
  22. Cell Syst. 2022 Apr 07. pii: S2405-4712(22)00128-4. [Epub ahead of print]
    Ligand-receptor promiscuity enables cellular addressing.
    Christina J Su, Arvind Murugan, James M Linton, Akshay Yeluri, Justin Bois, Heidi Klumpe, Matthew A Langley, Yaron E Antebi, Michael B Elowitz.
      In multicellular organisms, secreted ligands selectively activate, or "address," specific target cell populations to control cell fate decision-making and other processes. Key cell-cell communication pathways use multiple promiscuously interacting ligands and receptors, provoking the question of how addressing specificity can emerge from molecular promiscuity. To investigate this issue, we developed a general mathematical modeling framework based on the bone morphogenetic protein (BMP) pathway architecture. We find that promiscuously interacting ligand-receptor systems allow a small number of ligands, acting in combinations, to address a larger number of individual cell types, defined by their receptor expression profiles. Promiscuous systems outperform seemingly more specific one-to-one signaling architectures in addressing capability. Combinatorial addressing extends to groups of cell types, is robust to receptor expression noise, grows more powerful with increases in the number of receptor variants, and is maximized by specific biochemical parameter relationships. Together, these results identify design principles governing cellular addressing by ligand combinations.
    Keywords:  BMP; bone morphogenetic protein; cell-type specificity; combinatorial signaling; communication systems; information theory; ligand-receptor interactions; promiscuity; signal processing; signaling pathways
    DOI:  https://doi.org/10.1016/j.cels.2022.03.001
  23. Cell Metab. 2022 Apr 09. pii: S1550-4131(22)00125-5. [Epub ahead of print]
    Evaluating human genetic support for hypothesized metabolic disease genes.
    Peter Dornbos, Preeti Singh, Dong-Keun Jang, Anubha Mahajan, Sudha B Biddinger, Jerome I Rotter, Mark I McCarthy, Jason Flannick.
      We investigate the extent to which human genetic data are incorporated into studies that hypothesize novel links between genes and metabolic disease. To lower the barriers to using genetic data, we present an approach to enable researchers to evaluate human genetic support for experimentally determined hypotheses.
    DOI:  https://doi.org/10.1016/j.cmet.2022.03.011
  24. J Clin Invest. 2022 Apr 15. pii: e157560. [Epub ahead of print]132(8): 1-5
    Mitochondria and the future of RASopathies: the emergence of bioenergetics.
    Maria I Kontaridis, Saravanakkumar Chennappan.
      RASopathies are a family of rare autosomal dominant disorders that affect the canonical Ras/MAPK signaling pathway and manifest as neurodevelopmental systemic syndromes, including Costello syndrome (CS). In this issue of the JCI, Dard et al. describe the molecular determinants of CS using a myriad of genetically modified models, including mice expressing HRAS p.G12S, patient-derived skin fibroblasts, hiPSC-derived human cardiomyocytes, an HRAS p.G12V zebrafish model, and human lentivirally induced fibroblasts overexpressing HRAS p.G12S or HRAS p.G12A. Mitochondrial proteostasis and oxidative phosphorylation were altered in CS, and inhibition of the AMPK signaling pathway mediated bioenergetic changes. Importantly, the pharmacological induction of this pathway restored cardiac function and reduced the developmental defects associated with CS. These findings identify a role for altered bioenergetics and provide insights into more effective treatment strategies for patients with RASopathies.
    DOI:  https://doi.org/10.1172/JCI157560
  25. Science. 2022 Apr 15. 376(6590): eabh1623
    Sphingolipids control dermal fibroblast heterogeneity.
    Laura Capolupo, Irina Khven, Alex R Lederer, Luigi Mazzeo, Galina Glousker, Sylvia Ho, Francesco Russo, Jonathan Paz Montoya, Dhaka R Bhandari, Andrew P Bowman, Shane R Ellis, Romain Guiet, Olivier Burri, Johanna Detzner, Johannes Muthing, Krisztian Homicsko, François Kuonen, Michel Gilliet, Bernhard Spengler, Ron M A Heeren, G Paolo Dotto, Gioele La Manno, Giovanni D'Angelo.
      Human cells produce thousands of lipids that change during cell differentiation and can vary across individual cells of the same type. However, we are only starting to characterize the function of these cell-to-cell differences in lipid composition. Here, we measured the lipidomes and transcriptomes of individual human dermal fibroblasts by coupling high-resolution mass spectrometry imaging with single-cell transcriptomics. We found that the cell-to-cell variations of specific lipid metabolic pathways contribute to the establishment of cell states involved in the organization of skin architecture. Sphingolipid composition is shown to define fibroblast subpopulations, with sphingolipid metabolic rewiring driving cell-state transitions. Therefore, cell-to-cell lipid heterogeneity affects the determination of cell states, adding a new regulatory component to the self-organization of multicellular systems.
    DOI:  https://doi.org/10.1126/science.abh1623
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