bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–05–07
fifty-five papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. SEL1L-HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool.
  2. Single-cell analysis reveals inflammatory interactions driving macular degeneration.
  3. Massively parallel base editing to map variant effects in human hematopoiesis.
  4. Single-cell RNA-seq uncovers dynamic processes orchestrated by RNA-binding protein DDX43 in chromatin remodeling during spermiogenesis.
  5. Growing apart, staying connected.
  6. Cutting Edge: IL-21 and Tissue-Specific Signals Instruct Tbet+CD11c+ B Cell Development following Viral Infection.
  7. Generation of a novel synthetic CD8+ T cell state that leads to tumor control in mice.
  8. PPAR-γ regulates the effector function of human T helper 9 cells by promoting glycolysis.
  9. Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation.
  10. Organism-wide, cell-type-specific secretome mapping of exercise training in mice.
  11. Mediterranean mechanisms of longevity.
  12. Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome.
  13. Transcription factor induction of vascular blood stem cell niches in vivo.
  14. Mechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex.
  15. Reduced hepatic bradykinin degradation accounts for cold-induced BAT thermogenesis and WAT browning in male mice.
  16. Efficient prime editing in mouse brain, liver and heart with dual AAVs.
  17. The Fgf/Erf/NCoR1/2 repressive axis controls trophoblast cell fate.
  18. Neurotransmitters arrive to control systemic autoimmunity.
  19. Single-cell RNA sequencing reveals the fragility of male spermatogenic cells to Zika virus-induced complement activation.
  20. Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis.
  21. Peptide-mediated delivery of CRISPR enzymes for the efficient editing of primary human lymphocytes.
  22. Oligomeric scaffolding for curvature generation by ER tubule-forming proteins.
  23. Unearthing the Rosetta Stone of public antibody responses.
  24. Nanopore sequencing identifies a higher frequency and expanded spectrum of mitochondrial DNA deletion mutations in human aging.
  25. Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling.
  26. The road to death: Caspases, cleavage, and pores.
  27. How menopause reshapes the brain.
  28. Catch bond models may explain how force amplifies TCR signaling and antigen discrimination.
  29. Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease.
  30. Molecular basis of translation termination at noncanonical stop codons in human mitochondria.
  31. A DddA ortholog-based and transactivator-assisted nuclear and mitochondrial cytosine base editors with expanded target compatibility.
  32. Innate immune cell genetic risk factors are linked to COVID-19 severity.
  33. Refugee kids find more friends in diverse classrooms.
  34. 'Game changer' method lets scientists peer into mice.
  35. Chemical imaging reveals diverse functions of tricarboxylic acid metabolites in root growth and development.
  36. Deficiencies and Dysregulation of STAT Pathways That Drive Inborn Errors of Immunity: Lessons from Patients and Mouse Models of Disease.
  37. Methionine restriction constrains lipoylation and activates mitochondria for nitrogenic synthesis of amino acids.
  38. Gut microbiome dysbiosis across early Parkinson's disease, REM sleep behavior disorder and their first-degree relatives.
  39. TMEM106B regulates microglial proliferation and survival in response to demyelination.
  40. Dynamic and stable hippocampal representations of social identity and reward expectation support associative social memory in male mice.
  41. Identification of biomarkers for glycaemic deterioration in type 2 diabetes.
  42. Reconstruction of the cell pseudo-space from single-cell RNA sequencing data with scSpace.
  43. Remote control of autophagy and metabolism in the liver.
  44. The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.
  45. Unmasking the elusive erythropoietin-producing 'Norn' cell.
  46. Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids.
  47. Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis.
  48. Unjamming tumour cell invasion through cGAS-STING.
  49. New cellular 'organelle' discovered inside fruit-fly intestines.
  50. Plasma membrane preassociation drives β-arrestin coupling to receptors and activation.
  51. Morphodynamical cell state description via live-cell imaging trajectory embedding.
  52. Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice.
  53. Structure of the most abundant human gut virus.
  54. A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
  55. Coupling of protein condensates to ordered lipid domains determines functional membrane organization.
  1. Nat Cell Biol. 2023 May 04.
    SEL1L-HRD1 endoplasmic reticulum-associated degradation controls STING-mediated innate immunity by limiting the size of the activable STING pool.
    Yewei Ji, Yuan Luo, Yating Wu, Yao Sun, Lianfeng Zhao, Zhen Xue, Mengqi Sun, Xiaoqiong Wei, Zinan He, Shuangcheng Alivia Wu, Liangguang Leo Lin, You Lu, Lei Chang, Fei Chen, Siyu Chen, Wei Qian, Xiaoxi Xu, Shengnuo Chen, Dongli Pan, Zhangsen Zhou, Sheng Xia, Chih-Chi Andrew Hu, Tingbo Liang, Ling Qi.
      Stimulator of interferon genes (STING) orchestrates the production of proinflammatory cytokines in response to cytosolic double-stranded DNA; however, the pathophysiological significance and molecular mechanism underlying the folding and maturation of nascent STING protein at the endoplasmic reticulum (ER) remain unknown. Here we report that the SEL1L-HRD1 protein complex-the most conserved branch of ER-associated degradation (ERAD)-is a negative regulator of the STING innate immunity by ubiquitinating and targeting nascent STING protein for proteasomal degradation in the basal state. SEL1L or HRD1 deficiency in macrophages specifically amplifies STING signalling and immunity against viral infection and tumour growth. Mechanistically, nascent STING protein is a bona fide substrate of SEL1L-HRD1 in the basal state, uncoupled from ER stress or its sensor inositol-requiring enzyme 1α. Hence, our study not only establishes a key role of SEL1L-HRD1 ERAD in innate immunity by limiting the size of the activable STING pool, but identifies a regulatory mechanism and therapeutic approach to targeting STING.
    DOI:  https://doi.org/10.1038/s41556-023-01138-4
  2. Nat Commun. 2023 May 05. 14(1): 2589
    Single-cell analysis reveals inflammatory interactions driving macular degeneration.
    Manik Kuchroo, Marcello DiStasio, Eric Song, Eda Calapkulu, Le Zhang, Maryam Ige, Amar H Sheth, Abdelilah Majdoubi, Madhvi Menon, Alexander Tong, Abhinav Godavarthi, Yu Xing, Scott Gigante, Holly Steach, Jessie Huang, Guillaume Huguet, Janhavi Narain, Kisung You, George Mourgkos, Rahul M Dhodapkar, Matthew J Hirn, Bastian Rieck, Guy Wolf, Smita Krishnaswamy, Brian P Hafler.
      Due to commonalities in pathophysiology, age-related macular degeneration (AMD) represents a uniquely accessible model to investigate therapies for neurodegenerative diseases, leading us to examine whether pathways of disease progression are shared across neurodegenerative conditions. Here we use single-nucleus RNA sequencing to profile lesions from 11 postmortem human retinas with age-related macular degeneration and 6 control retinas with no history of retinal disease. We create a machine-learning pipeline based on recent advances in data geometry and topology and identify activated glial populations enriched in the early phase of disease. Examining single-cell data from Alzheimer's disease and progressive multiple sclerosis with our pipeline, we find a similar glial activation profile enriched in the early phase of these neurodegenerative diseases. In late-stage age-related macular degeneration, we identify a microglia-to-astrocyte signaling axis mediated by interleukin-1β which drives angiogenesis characteristic of disease pathogenesis. We validated this mechanism using in vitro and in vivo assays in mouse, identifying a possible new therapeutic target for AMD and possibly other neurodegenerative conditions. Thus, due to shared glial states, the retina provides a potential system for investigating therapeutic approaches in neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41467-023-37025-7
  3. Cell. 2023 Apr 27. pii: S0092-8674(23)00332-X. [Epub ahead of print]
    Massively parallel base editing to map variant effects in human hematopoiesis.
    Jorge D Martin-Rufino, Nicole Castano, Michael Pang, Emanuelle I Grody, Samantha Joubran, Alexis Caulier, Lara Wahlster, Tongqing Li, Xiaojie Qiu, Anna Maria Riera-Escandell, Gregory A Newby, Aziz Al'Khafaji, Santosh Chaudhary, Susan Black, Chen Weng, Glen Munson, David R Liu, Marcin W Wlodarski, Kacie Sims, Jamie H Oakley, Ross M Fasano, Ramnik J Xavier, Eric S Lander, Daryl E Klein, Vijay G Sankaran.
      Systematic evaluation of the impact of genetic variants is critical for the study and treatment of human physiology and disease. While specific mutations can be introduced by genome engineering, we still lack scalable approaches that are applicable to the important setting of primary cells, such as blood and immune cells. Here, we describe the development of massively parallel base-editing screens in human hematopoietic stem and progenitor cells. Such approaches enable functional screens for variant effects across any hematopoietic differentiation state. Moreover, they allow for rich phenotyping through single-cell RNA sequencing readouts and separately for characterization of editing outcomes through pooled single-cell genotyping. We efficiently design improved leukemia immunotherapy approaches, comprehensively identify non-coding variants modulating fetal hemoglobin expression, define mechanisms regulating hematopoietic differentiation, and probe the pathogenicity of uncharacterized disease-associated variants. These strategies will advance effective and high-throughput variant-to-function mapping in human hematopoiesis to identify the causes of diverse diseases.
    Keywords:  base editing; differentiation; functional screens; genome engineering; hematopoiesis; hematopoietic stem cell; primary cells; single-cell genomics
    DOI:  https://doi.org/10.1016/j.cell.2023.03.035
  4. Nat Commun. 2023 04 29. 14(1): 2499
    Single-cell RNA-seq uncovers dynamic processes orchestrated by RNA-binding protein DDX43 in chromatin remodeling during spermiogenesis.
    Huanhuan Tan, Weixu Wang, Congjin Zhou, Yanfeng Wang, Shu Zhang, Pinglan Yang, Rui Guo, Wei Chen, Jinwen Zhang, Lan Ye, Yiqiang Cui, Ting Ni, Ke Zheng.
      Mammalian spermatogenesis shows prominent chromatin and transcriptomic switches in germ cells, but it is unclear how such dynamics are controlled. Here we identify RNA helicase DDX43 as an essential regulator of the chromatin remodeling process during spermiogenesis. Testis-specific Ddx43 knockout mice show male infertility with defective histone-to-protamine replacement and post-meiotic chromatin condensation defects. The loss of its ATP hydrolysis activity by a missense mutation replicates the infertility phenotype in global Ddx43 knockout mice. Single-cell RNA sequencing analyses of germ cells depleted of Ddx43 or expressing the Ddx43 ATPase-dead mutant reveals that DDX43 regulates dynamic RNA regulatory processes that underlie spermatid chromatin remodeling and differentiation. Transcriptomic profiling focusing on early-stage spermatids combined with enhanced crosslinking immunoprecipitation and sequencing further identifies Elfn2 as DDX43-targeted hub gene. These findings illustrate an essential role for DDX43 in spermiogenesis and highlight the single-cell-based strategy to dissect cell-state-specific regulation of male germline development.
    DOI:  https://doi.org/10.1038/s41467-023-38199-w
  5. Science. 2023 May 05. 380(6644): 554
    Growing apart, staying connected.
    Janaynne Carvalho do Amaral.
      
    DOI:  https://doi.org/10.1126/science.adi4923
  6. J Immunol. 2023 May 03. pii: ji2300027. [Epub ahead of print]
    Cutting Edge: IL-21 and Tissue-Specific Signals Instruct Tbet+CD11c+ B Cell Development following Viral Infection.
    Wenzhi Song, Gina M Sanchez, Daniel P Mayer, Holly N Blackburn, Irene Chernova, Richard A Flavell, Jason S Weinstein, Joe Craft.
      Tbet+CD11c+ B cells, also known as age-associated B cells (ABCs), are pivotal contributors to humoral immunity following infection and in autoimmunity, yet their in vivo generation is incompletely understood. We used a mouse model of systemic acute lymphocytic choriomeningitis virus infection to examine the developmental requirements of ABCs that emerged in the spleen and liver. IL-21 signaling through STAT3 was indispensable for ABC development. In contrast, IFN-γ signaling through STAT1 was required for B cell activation and proliferation. Mice that underwent splenectomy or were deficient in lymphotoxin α generated hepatic ABCs despite the lack of secondary lymphoid organ contributions, suggesting that the liver supported de novo generation of these cells separately from their development in lymphoid organs. Thus, IFN-γ and IL-21 signaling have distinct, stage-specific roles in ABC differentiation, while the tissue microenvironment provides additional cues necessary for their development.
    DOI:  https://doi.org/10.4049/jimmunol.2300027
  7. Nat Immunol. 2023 05;24(5): 755-756
    Generation of a novel synthetic CD8+ T cell state that leads to tumor control in mice.
      
    DOI:  https://doi.org/10.1038/s41590-023-01478-1
  8. Nat Commun. 2023 04 29. 14(1): 2471
    PPAR-γ regulates the effector function of human T helper 9 cells by promoting glycolysis.
    Nicole L Bertschi, Oliver Steck, Fabian Luther, Cecilia Bazzini, Leonhard von Meyenn, Stefanie Schärli, Angela Vallone, Andrea Felser, Irene Keller, Olivier Friedli, Stefan Freigang, Nadja Begré, Susanne Radonjic-Hoesli, Cristina Lamos, Max Philip Gabutti, Michael Benzaquen, Markus Laimer, Dagmar Simon, Jean-Marc Nuoffer, Christoph Schlapbach.
      T helper 9 (TH9) cells promote allergic tissue inflammation and express the type 2 cytokines, IL-9 and IL-13, as well as the transcription factor, PPAR-γ. However, the functional role of PPAR-γ in human TH9 cells remains unknown. Here, we demonstrate that PPAR-γ drives activation-induced glycolysis, which, in turn, promotes the expression of IL-9, but not IL-13, in an mTORC1-dependent manner. In vitro and ex vivo experiments show that the PPAR-γ-mTORC1-IL-9 pathway is active in TH9 cells in human skin inflammation. Additionally, we find dynamic regulation of tissue glucose levels in acute allergic skin inflammation, suggesting that in situ glucose availability is linked to distinct immunological functions in vivo. Furthermore, paracrine IL-9 induces expression of the lactate transporter, MCT1, in TH cells and promotes their aerobic glycolysis and proliferative capacity. Altogether, our findings uncover a hitherto unknown relationship between PPAR-γ-dependent glucose metabolism and pathogenic effector functions in human TH9 cells.
    DOI:  https://doi.org/10.1038/s41467-023-38233-x
  9. Nat Commun. 2023 May 05. 14(1): 2610
    Neutrophil metabolomics in severe COVID-19 reveal GAPDH as a suppressor of neutrophil extracellular trap formation.
    Yafeng Li, Jessica S Hook, Qing Ding, Xue Xiao, Stephen S Chung, Marcel Mettlen, Lin Xu, Jessica G Moreland, Michalis Agathocleous.
      Severe COVID-19 is characterized by an increase in the number and changes in the function of innate immune cells including neutrophils. However, it is not known how the metabolome of immune cells changes in patients with COVID-19. To address these questions, we analyzed the metabolome of neutrophils from patients with severe or mild COVID-19 and healthy controls. We identified widespread dysregulation of neutrophil metabolism with disease progression including in amino acid, redox, and central carbon metabolism. Metabolic changes in neutrophils from patients with severe COVID-19 were consistent with reduced activity of the glycolytic enzyme GAPDH. Inhibition of GAPDH blocked glycolysis and promoted pentose phosphate pathway activity but blunted the neutrophil respiratory burst. Inhibition of GAPDH was sufficient to cause neutrophil extracellular trap (NET) formation which required neutrophil elastase activity. GAPDH inhibition increased neutrophil pH, and blocking this increase prevented cell death and NET formation. These findings indicate that neutrophils in severe COVID-19 have an aberrant metabolism which can contribute to their dysfunction. Our work also shows that NET formation, a pathogenic feature of many inflammatory diseases, is actively suppressed in neutrophils by a cell-intrinsic mechanism controlled by GAPDH.
    DOI:  https://doi.org/10.1038/s41467-023-37567-w
  10. Cell Metab. 2023 Apr 28. pii: S1550-4131(23)00138-9. [Epub ahead of print]
    Organism-wide, cell-type-specific secretome mapping of exercise training in mice.
    Wei Wei, Nicholas M Riley, Xuchao Lyu, Xiaotao Shen, Jing Guo, Steffen H Raun, Meng Zhao, Maria Dolores Moya-Garzon, Himanish Basu, Alan Sheng-Hwa Tung, Veronica L Li, Wentao Huang, Amanda L Wiggenhorn, Katrin J Svensson, Michael P Snyder, Carolyn R Bertozzi, Jonathan Z Long.
      There is a significant interest in identifying blood-borne factors that mediate tissue crosstalk and function as molecular effectors of physical activity. Although past studies have focused on an individual molecule or cell type, the organism-wide secretome response to physical activity has not been evaluated. Here, we use a cell-type-specific proteomic approach to generate a 21-cell-type, 10-tissue map of exercise training-regulated secretomes in mice. Our dataset identifies >200 exercise training-regulated cell-type-secreted protein pairs, the majority of which have not been previously reported. Pdgfra-cre-labeled secretomes were the most responsive to exercise training. Finally, we show anti-obesity, anti-diabetic, and exercise performance-enhancing activities for proteoforms of intracellular carboxylesterases whose secretion from the liver is induced by exercise training.
    Keywords:  CES2; cell type; energy metabolism; exercise; exercise performance; hepatokine; obesity; secretome; tissue crosstalk
    DOI:  https://doi.org/10.1016/j.cmet.2023.04.011
  11. Nat Cell Biol. 2023 May 01.
    Mediterranean mechanisms of longevity.
    Alexander Richard Mendenhall.
      
    DOI:  https://doi.org/10.1038/s41556-023-01115-x
  12. Nat Commun. 2023 04 29. 14(1): 2481
    Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome.
    Alexandra Barry, Michelle T McNulty, Xiaoyuan Jia, Yask Gupta, Hanna Debiec, Yang Luo, China Nagano, Tomoko Horinouchi, Seulgi Jung, Manuela Colucci, Dina F Ahram, Adele Mitrotti, Aditi Sinha, Nynke Teeninga, Gina Jin, Shirlee Shril, Gianluca Caridi, Monica Bodria, Tze Y Lim, Rik Westland, Francesca Zanoni, Maddalena Marasa, Daniel Turudic, Mario Giordano, Loreto Gesualdo, Riccardo Magistroni, Isabella Pisani, Enrico Fiaccadori, Jana Reiterova, Silvio Maringhini, William Morello, Giovanni Montini, Patricia L Weng, Francesco Scolari, Marijan Saraga, Velibor Tasic, Domenica Santoro, Joanna A E van Wijk, Danko Milošević, Yosuke Kawai, Krzysztof Kiryluk, Martin R Pollak, Ali Gharavi, Fangmin Lin, Ana Cristina Simœs E Silva, Ruth J F Loos, Eimear E Kenny, Michiel F Schreuder, Aleksandra Zurowska, Claire Dossier, Gema Ariceta, Magdalena Drozynska-Duklas, Julien Hogan, Augustina Jankauskiene, Friedhelm Hildebrandt, Larisa Prikhodina, Kyuyoung Song, Arvind Bagga, Hae Cheong, Gian Marco Ghiggeri, Prayong Vachvanichsanong, Kandai Nozu, Dongwon Lee, Marina Vivarelli, Soumya Raychaudhuri, Katsushi Tokunaga, Simone Sanna-Cherchi, Pierre Ronco, Kazumoto Iijima, Matthew G Sampson.
      Pediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.
    DOI:  https://doi.org/10.1038/s41467-023-37985-w
  13. Dev Cell. 2023 Apr 25. pii: S1534-5807(23)00160-0. [Epub ahead of print]
    Transcription factor induction of vascular blood stem cell niches in vivo.
    Elliott J Hagedorn, Julie R Perlin, Rebecca J Freeman, Samuel J Wattrus, Tianxiao Han, Clara Mao, Ji Wook Kim, Inés Fernández-Maestre, Madeleine L Daily, Christopher D'Amato, Michael J Fairchild, Raquel Riquelme, Brian Li, Dana A V E Ragoonanan, Khaliun Enkhbayar, Emily L Henault, Helen G Wang, Shelby E Redfield, Samantha H Collins, Asher Lichtig, Song Yang, Yi Zhou, Balvir Kunar, Jesus Maria Gomez-Salinero, Thanh T Dinh, Junliang Pan, Karoline Holler, Henry A Feldman, Eugene C Butcher, Alexander van Oudenaarden, Shahin Rafii, J Philipp Junker, Leonard I Zon.
      The hematopoietic niche is a supportive microenvironment composed of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses in zebrafish, we define a conserved gene expression signature and cis-regulatory landscape that are unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code that involves members of the Ets, Sox, and nuclear hormone receptor families and is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance, and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.
    Keywords:  blood stem cell niche; hematopoietic development; niche endothelial cells; reprogramming; vascular endothelium; zebrafish
    DOI:  https://doi.org/10.1016/j.devcel.2023.04.007
  14. Nat Commun. 2023 May 03. 14(1): 2556
    Mechanism of assembly, activation and lysine selection by the SIN3B histone deacetylase complex.
    Mandy S M Wan, Reyhan Muhammad, Marios G Koliopoulos, Theodoros I Roumeliotis, Jyoti S Choudhary, Claudio Alfieri.
      Lysine acetylation in histone tails is a key post-translational modification that controls transcription activation. Histone deacetylase complexes remove histone acetylation, thereby repressing transcription and regulating the transcriptional output of each gene. Although these complexes are drug targets and crucial regulators of organismal physiology, their structure and mechanisms of action are largely unclear. Here, we present the structure of a complete human SIN3B histone deacetylase holo-complex with and without a substrate mimic. Remarkably, SIN3B encircles the deacetylase and contacts its allosteric basic patch thereby stimulating catalysis. A SIN3B loop inserts into the catalytic tunnel, rearranges to accommodate the acetyl-lysine moiety, and stabilises the substrate for specific deacetylation, which is guided by a substrate receptor subunit. Our findings provide a model of specificity for a main transcriptional regulator conserved from yeast to human and a resource of protein-protein interactions for future drug designs.
    DOI:  https://doi.org/10.1038/s41467-023-38276-0
  15. Nat Commun. 2023 May 02. 14(1): 2523
    Reduced hepatic bradykinin degradation accounts for cold-induced BAT thermogenesis and WAT browning in male mice.
    Fei Xiao, Haizhou Jiang, Zi Li, Xiaoxue Jiang, Shanghai Chen, Yuguo Niu, Hanrui Yin, Yousheng Shu, Bo Peng, Wei Lu, Xiaoying Li, Zhigang Li, Shujue Lan, Xiaoyan Xu, Feifan Guo.
      An important role for liver in the regulation of adipose tissue thermogenesis upon cold exposure has been suggested; however, the underlying mechanisms remain incompletely defined. Here, we identify elevated serum bradykinin levels in response to acute cold exposure in male mice. A bolus of anti-bradykinin antibodies reduces body temperature during acute cold exposure, whereas bradykinin has the opposite effect. We demonstrate that bradykinin induces brown adipose tissue thermogenesis and white adipose tissue browning, and bradykinin increases uncoupling protein 1 (UCP1) expression in adipose tissue. The bradykinin B2 receptor (B2R), adrenergic signaling and nitric oxide signaling are involved in regulating bradykinin-increased UCP1 expression. Moreover, acute cold exposure inhibits hepatic prolyl endopeptidase (PREP) activity, causing reduced liver bradykinin degradation and increased serum bradykinin levels. Finally, by blocking the breakdown of bradykinin, angiotensin-converting enzyme inhibitors (ACEIs) increase serum bradykinin levels and induce brown adipose tissue thermogenesis and white adipose tissue browning via B2R. Collectively, our data provide new insights into the mechanisms underlying organ crosstalk in whole-body physiology control during cold exposure and also suggest bradykinin as a possible anti-obesity target.
    DOI:  https://doi.org/10.1038/s41467-023-38141-0
  16. Nat Biotechnol. 2023 May 04.
    Efficient prime editing in mouse brain, liver and heart with dual AAVs.
    Jessie R Davis, Samagya Banskota, Jonathan M Levy, Gregory A Newby, Xiao Wang, Andrew V Anzalone, Andrew T Nelson, Peter J Chen, Andrew D Hennes, Meirui An, Heejin Roh, Peyton B Randolph, Kiran Musunuru, David R Liu.
      Realizing the promise of prime editing for the study and treatment of genetic disorders requires efficient methods for delivering prime editors (PEs) in vivo. Here we describe the identification of bottlenecks limiting adeno-associated virus (AAV)-mediated prime editing in vivo and the development of AAV-PE vectors with increased PE expression, prime editing guide RNA stability and modulation of DNA repair. The resulting dual-AAV systems, v1em and v3em PE-AAV, enable therapeutically relevant prime editing in mouse brain (up to 42% efficiency in cortex), liver (up to 46%) and heart (up to 11%). We apply these systems to install putative protective mutations in vivo for Alzheimer's disease in astrocytes and for coronary artery disease in hepatocytes. In vivo prime editing with v3em PE-AAV caused no detectable off-target effects or significant changes in liver enzymes or histology. Optimized PE-AAV systems support the highest unenriched levels of in vivo prime editing reported to date, facilitating the study and potential treatment of diseases with a genetic component.
    DOI:  https://doi.org/10.1038/s41587-023-01758-z
  17. Nat Commun. 2023 May 04. 14(1): 2559
    The Fgf/Erf/NCoR1/2 repressive axis controls trophoblast cell fate.
    Andreas Lackner, Michael Müller, Magdalena Gamperl, Delyana Stoeva, Olivia Langmann, Henrieta Papuchova, Elisabeth Roitinger, Gerhard Dürnberger, Richard Imre, Karl Mechtler, Paulina A Latos.
      Placental development relies on coordinated cell fate decisions governed by signalling inputs. However, little is known about how signalling cues are transformed into repressive mechanisms triggering lineage-specific transcriptional signatures. Here, we demonstrate that upon inhibition of the Fgf/Erk pathway in mouse trophoblast stem cells (TSCs), the Ets2 repressor factor (Erf) interacts with the Nuclear Receptor Co-Repressor Complex 1 and 2 (NCoR1/2) and recruits it to key trophoblast genes. Genetic ablation of Erf or Tbl1x (a component of the NCoR1/2 complex) abrogates the Erf/NCoR1/2 interaction. This leads to mis-expression of Erf/NCoR1/2 target genes, resulting in a TSC differentiation defect. Mechanistically, Erf regulates expression of these genes by recruiting the NCoR1/2 complex and decommissioning their H3K27ac-dependent enhancers. Our findings uncover how the Fgf/Erf/NCoR1/2 repressive axis governs cell fate and placental development, providing a paradigm for Fgf-mediated transcriptional control.
    DOI:  https://doi.org/10.1038/s41467-023-38101-8
  18. Cell Metab. 2023 May 02. pii: S1550-4131(23)00131-6. [Epub ahead of print]35(5): 728-729
    Neurotransmitters arrive to control systemic autoimmunity.
    Marc Scherlinger, George C Tsokos.
      Immune cell microenvironment plays a major role in the aberrant function of immune cells in systemic lupus erythematosus. Zeng and co-authors show that in human and murine lupus, splenic stromal cell-derived acetylcholine switches B cell metabolism to fatty acid oxidation and promotes B cell autoreactivity and disease development.
    DOI:  https://doi.org/10.1016/j.cmet.2023.04.004
  19. Nat Commun. 2023 04 29. 14(1): 2476
    Single-cell RNA sequencing reveals the fragility of male spermatogenic cells to Zika virus-induced complement activation.
    Wei Yang, Li-Bo Liu, Feng-Liang Liu, Yan-Hua Wu, Zi-Da Zhen, Dong-Ying Fan, Zi-Yang Sheng, Zheng-Ran Song, Jia-Tong Chang, Yong-Tang Zheng, Jing An, Pei-Gang Wang.
      Zika virus (ZIKV) is a potential threat to male reproductive health but the mechanisms underlying its influence on testes during ZIKV infection remain obscure. To address this question, we perform single-cell RNA sequencing using testes from ZIKV-infected mice. The results reveal the fragility of spermatogenic cells, especially spermatogonia, to ZIKV infection and show that the genes of the complement system are significantly upregulated mainly in infiltrated S100A4 + monocytes/macrophages. Complement activation and its contribution to testicular damage are validated by ELISA, RT‒qPCR and IFA and further verify in ZIKV-infected northern pigtailed macaques by RNA genome sequencing and IFA, suggesting that this might be the common response to ZIKV infection in primates. On this basis, we test the complement inhibitor C1INH and S100A4 inhibitors sulindac and niclosamide for their effects on testis protection. C1INH alleviates the pathological change in the testis but deteriorates ZIKV infection in general. In contrast, niclosamide effectively reduces S100A4 + monocyte/macrophage infiltration, inhibits complement activation, alleviates testicular damage, and rescues the fertility of male mice from ZIKV infection. This discovery therefore encourages male reproductive health protection during the next ZIKV epidemic.
    DOI:  https://doi.org/10.1038/s41467-023-38223-z
  20. Sci Immunol. 2023 May 12. 8(83): eadh3455
    Cytokinopathy with aberrant cytotoxic lymphocytes and profibrotic myeloid response in SARS-CoV-2 mRNA vaccine-associated myocarditis.
    Anis Barmada, Jon Klein, Anjali Ramaswamy, Nina N Brodsky, Jillian R Jaycox, Hassan Sheikha, Kate M Jones, Victoria Habet, Melissa Campbell, Tomokazu S Sumida, Amy Kontorovich, Dusan Bogunovic, Carlos R Oliveira, Jeremy Steele, E Kevin Hall, Mario Pena-Hernandez, Valter Monteiro, Carolina Lucas, Aaron M Ring, Saad B Omer, Akiko Iwasaki, Inci Yildirim, Carrie L Lucas.
      Rare immune-mediated cardiac tissue inflammation can occur after vaccination, including after SARS-CoV-2 mRNA vaccines. However, the underlying immune cellular and molecular mechanisms driving this pathology remain poorly understood. Here, we investigated a cohort of patients who developed myocarditis and/or pericarditis with elevated troponin, B-type natriuretic peptide, and C-reactive protein levels as well as cardiac imaging abnormalities shortly after SARS-CoV-2 mRNA vaccination. Contrary to early hypotheses, patients did not demonstrate features of hypersensitivity myocarditis, nor did they have exaggerated SARS-CoV-2-specific or neutralizing antibody responses consistent with a hyperimmune humoral mechanism. We additionally found no evidence of cardiac-targeted autoantibodies. Instead, unbiased systematic immune serum profiling revealed elevations in circulating interleukins (IL-1β, IL-1RA, and IL-15), chemokines (CCL4, CXCL1, and CXCL10), and matrix metalloproteases (MMP1, MMP8, MMP9, and TIMP1). Subsequent deep immune profiling using single-cell RNA and repertoire sequencing of peripheral blood mononuclear cells during acute disease revealed expansion of activated CXCR3+ cytotoxic T cells and NK cells, both phenotypically resembling cytokine-driven killer cells. In addition, patients displayed signatures of inflammatory and profibrotic CCR2+ CD163+ monocytes, coupled with elevated serum-soluble CD163, that may be linked to the late gadolinium enhancement on cardiac MRI, which can persist for months after vaccination. Together, our results demonstrate up-regulation in inflammatory cytokines and corresponding lymphocytes with tissue-damaging capabilities, suggesting a cytokine-dependent pathology, which may further be accompanied by myeloid cell-associated cardiac fibrosis. These findings likely rule out some previously proposed mechanisms of mRNA vaccine--associated myopericarditis and point to new ones with relevance to vaccine development and clinical care.
    DOI:  https://doi.org/10.1126/sciimmunol.adh3455
  21. Nat Biomed Eng. 2023 Apr 25.
    Peptide-mediated delivery of CRISPR enzymes for the efficient editing of primary human lymphocytes.
    Dana V Foss, Joseph J Muldoon, David N Nguyen, Daniel Carr, Srishti U Sahu, John M Hunsinger, Stacia K Wyman, Netravathi Krishnappa, Rima Mendonsa, Elaine V Schanzer, Brian R Shy, Vivasvan S Vykunta, Vincent Allain, Zhongmei Li, Alexander Marson, Justin Eyquem, Ross C Wilson.
      CRISPR-mediated genome editing of primary human lymphocytes is typically carried out via electroporation, which can be cytotoxic, cumbersome and costly. Here we show that the yields of edited primary human lymphocytes can be increased substantially by delivering a CRISPR ribonucleoprotein mixed with an amphiphilic peptide identified through screening. We evaluated the performance of this simple delivery method by knocking out genes in T cells, B cells and natural killer cells via the delivery of Cas9 or Cas12a ribonucleoproteins or an adenine base editor. We also show that peptide-mediated ribonucleoprotein delivery paired with an adeno-associated-virus-mediated homology-directed repair template can introduce a chimaeric antigen receptor gene at the T-cell receptor α constant locus, and that the engineered cells display antitumour potency in mice. The method is minimally perturbative, does not require dedicated hardware, and is compatible with multiplexed editing via sequential delivery, which minimizes the risk of genotoxicity. The peptide-mediated intracellular delivery of ribonucleoproteins may facilitate the manufacturing of engineered T cells.
    DOI:  https://doi.org/10.1038/s41551-023-01032-2
  22. Nat Commun. 2023 May 05. 14(1): 2617
    Oligomeric scaffolding for curvature generation by ER tubule-forming proteins.
    Yun Xiang, Rui Lyu, Junjie Hu.
      The reticulons and receptor expression-enhancing proteins (REEPs) in the endoplasmic reticulum (ER) are necessary and sufficient for generating ER tubules. However, the mechanism of curvature generation remains elusive. Here, we systematically analyze components of the REEP family based on AI-predicted structures. In yeast REEP Yop1p, TM1/2 and TM3/4 form hairpins and TM2-4 exist as a bundle. Site-directed cross-linking reveals that TM2 and TM4 individually mediate homotypic dimerization, allowing further assembly into a curved shape. Truncated Yop1p lacking TM1 (equivalent to REEP1) retains the curvature-generating capability, undermining the role of the intrinsic wedge. Unexpectedly, both REEP1 and REEP5 fail to replace Yop1p in the maintenance of ER morphology, mostly due to a subtle difference in oligomerization tendency, which involves not only the TM domains, but also the TM-connecting cytosolic loop and previously neglected C-terminal helix. Several hereditary spastic paraplegia-causing mutations in REEP1 appear at the oligomeric interfaces identified here, suggesting compromised self-association of REEP as a pathogenic mechanism. These results indicate that membrane curvature stabilization by integral membrane proteins is dominantly achieved by curved, oligomeric scaffolding.
    DOI:  https://doi.org/10.1038/s41467-023-38294-y
  23. Sci Immunol. 2023 May 12. 8(83): eadi4342
    Unearthing the Rosetta Stone of public antibody responses.
    Gianvito Masi.
      Comprehensive profiling of humoral responses to viruses reveals that germline-encoded V gene motifs govern the emergence of recurrent antibody epitopes across individuals.
    DOI:  https://doi.org/10.1126/sciimmunol.adi4342
  24. Aging Cell. 2023 May 03. e13842
    Nanopore sequencing identifies a higher frequency and expanded spectrum of mitochondrial DNA deletion mutations in human aging.
    Amy R Vandiver, Austin N Hoang, Allen Herbst, Cathy C Lee, Judd M Aiken, Debbie McKenzie, Michael A Teitell, Winston Timp, Jonathan Wanagat.
      Mitochondrial DNA (mtDNA) deletion mutations cause many human diseases and are linked to age-induced mitochondrial dysfunction. Mapping the mutation spectrum and quantifying mtDNA deletion mutation frequency is challenging with next-generation sequencing methods. We hypothesized that long-read sequencing of human mtDNA across the lifespan would detect a broader spectrum of mtDNA rearrangements and provide a more accurate measurement of their frequency. We employed nanopore Cas9-targeted sequencing (nCATS) to map and quantitate mtDNA deletion mutations and develop analyses that are fit-for-purpose. We analyzed total DNA from vastus lateralis muscle in 15 males ranging from 20 to 81 years of age and substantia nigra from three 20-year-old and three 79-year-old men. We found that mtDNA deletion mutations detected by nCATS increased exponentially with age and mapped to a wider region of the mitochondrial genome than previously reported. Using simulated data, we observed that large deletions are often reported as chimeric alignments. To address this, we developed two algorithms for deletion identification which yield consistent deletion mapping and identify both previously reported and novel mtDNA deletion breakpoints. The identified mtDNA deletion frequency measured by nCATS correlates strongly with chronological age and predicts the deletion frequency as measured by digital PCR approaches. In substantia nigra, we observed a similar frequency of age-related mtDNA deletions to those observed in muscle samples, but noted a distinct spectrum of deletion breakpoints. NCATS-mtDNA sequencing allows the identification of mtDNA deletions on a single-molecule level, characterizing the strong relationship between mtDNA deletion frequency and chronological aging.
    Keywords:  DNA sequencing; aging; human; mitochondrial DNA; skeletal muscle; substantia nigra
    DOI:  https://doi.org/10.1111/acel.13842
  25. Nat Commun. 2023 May 05. 14(1): 2594
    Molecular determinants of inhibition of UCP1-mediated respiratory uncoupling.
    Antoine Gagelin, Corentin Largeau, Sandrine Masscheleyn, Mathilde S Piel, Daniel Calderón-Mora, Frédéric Bouillaud, Jérôme Hénin, Bruno Miroux.
      Brown adipose tissue expresses uncoupling protein 1 (UCP1), which dissipates energy as heat, making it a target for treating metabolic disorders. Here, we investigate how purine nucleotides inhibit respiration uncoupling by UCP1. Our molecular simulations predict that GDP and GTP bind UCP1 in the common substrate binding site in an upright orientation, where the base moiety interacts with conserved residues R92 and E191. We identify a triplet of uncharged residues, F88/I187/W281, forming hydrophobic contacts with nucleotides. In yeast spheroplast respiration assays, both I187A and W281A mutants increase the fatty acid-induced uncoupling activity of UCP1 and partially suppress the inhibition of UCP1 activity by nucleotides. The F88A/I187A/W281A triple mutant is overactivated by fatty acids even at high concentrations of purine nucleotides. In simulations, E191 and W281 interact with purine but not pyrimidine bases. These results provide a molecular understanding of the selective inhibition of UCP1 by purine nucleotides.
    DOI:  https://doi.org/10.1038/s41467-023-38219-9
  26. Sci Adv. 2023 04 28. 9(17): eadi2011
    The road to death: Caspases, cleavage, and pores.
    Vishva M Dixit.
      Vishva Dixit recounts his favorite discoveries after 30-plus years studying the proteins that allow infected, damaged, or obsolete cells to die.
    DOI:  https://doi.org/10.1126/sciadv.adi2011
  27. Nature. 2023 May;617(7959): 25-27
    How menopause reshapes the brain.
    Heidi Ledford.
      
    Keywords:  Brain; Funding; Medical research
    DOI:  https://doi.org/10.1038/d41586-023-01474-3
  28. Nat Commun. 2023 May 05. 14(1): 2616
    Catch bond models may explain how force amplifies TCR signaling and antigen discrimination.
    Hyun-Kyu Choi, Peiwen Cong, Chenghao Ge, Aswin Natarajan, Baoyu Liu, Yong Zhang, Kaitao Li, Muaz Nik Rushdi, Wei Chen, Jizhong Lou, Michelle Krogsgaard, Cheng Zhu.
      The TCR integrates forces in its triggering process upon interaction with pMHC. Force elicits TCR catch-slip bonds with strong pMHCs but slip-only bonds with weak pMHCs. We develop two models and apply them to analyze 55 datasets, demonstrating the models' ability to quantitatively integrate and classify a broad range of bond behaviors and biological activities. Comparing to a generic two-state model, our models can distinguish class I from class II MHCs and correlate their structural parameters with the TCR/pMHC's potency to trigger T cell activation. The models are tested by mutagenesis using an MHC and a TCR mutated to alter conformation changes. The extensive comparisons between theory and experiment provide model validation and testable hypothesis regarding specific conformational changes that control bond profiles, thereby suggesting structural mechanisms for the inner workings of the TCR mechanosensing machinery and plausible explanations of why and how force may amplify TCR signaling and antigen discrimination.
    DOI:  https://doi.org/10.1038/s41467-023-38267-1
  29. Nat Commun. 2023 May 04. 14(1): 2573
    Restoration of lysosomal acidification rescues autophagy and metabolic dysfunction in non-alcoholic fatty liver disease.
    Jialiu Zeng, Rebeca Acin-Perez, Essam A Assali, Andrew Martin, Alexandra J Brownstein, Anton Petcherski, Lucía Fernández-Del-Rio, Ruiqing Xiao, Chih Hung Lo, Michaël Shum, Marc Liesa, Xue Han, Orian S Shirihai, Mark W Grinstaff.
      Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. High levels of free fatty acids in the liver impair hepatic lysosomal acidification and reduce autophagic flux. We investigate whether restoration of lysosomal function in NAFLD recovers autophagic flux, mitochondrial function, and insulin sensitivity. Here, we report the synthesis of novel biodegradable acid-activated acidifying nanoparticles (acNPs) as a lysosome targeting treatment to restore lysosomal acidity and autophagy. The acNPs, composed of fluorinated polyesters, remain inactive at plasma pH, and only become activated in lysosomes after endocytosis. Specifically, they degrade at pH of ~6 characteristic of dysfunctional lysosomes, to further acidify and enhance the function of lysosomes. In established in vivo high fat diet mouse models of NAFLD, re-acidification of lysosomes via acNP treatment restores autophagy and mitochondria function to lean, healthy levels. This restoration, concurrent with reversal of fasting hyperglycemia and hepatic steatosis, indicates the potential use of acNPs as a first-in-kind therapeutic for NAFLD.
    DOI:  https://doi.org/10.1038/s41467-023-38165-6
  30. Science. 2023 May 05. 380(6644): 531-536
    Molecular basis of translation termination at noncanonical stop codons in human mitochondria.
    Martin Saurer, Marc Leibundgut, Hima Priyanka Nadimpalli, Alain Scaiola, Tanja Schönhut, Richard G Lee, Stefan J Siira, Oliver Rackham, René Dreos, Tea Lenarčič, Eva Kummer, David Gatfield, Aleksandra Filipovska, Nenad Ban.
      The genetic code that specifies the identity of amino acids incorporated into proteins during protein synthesis is almost universally conserved. Mitochondrial genomes feature deviations from the standard genetic code, including the reassignment of two arginine codons to stop codons. The protein required for translation termination at these noncanonical stop codons to release the newly synthesized polypeptides is not currently known. In this study, we used gene editing and ribosomal profiling in combination with cryo-electron microscopy to establish that mitochondrial release factor 1 (mtRF1) detects noncanonical stop codons in human mitochondria by a previously unknown mechanism of codon recognition. We discovered that binding of mtRF1 to the decoding center of the ribosome stabilizes a highly unusual conformation in the messenger RNA in which the ribosomal RNA participates in specific recognition of the noncanonical stop codons.
    DOI:  https://doi.org/10.1126/science.adf9890
  31. Mol Cell. 2023 Apr 30. pii: S1097-2765(23)00283-6. [Epub ahead of print]
    A DddA ortholog-based and transactivator-assisted nuclear and mitochondrial cytosine base editors with expanded target compatibility.
    Junfan Guo, Wenxia Yu, Min Li, Hongyu Chen, Jie Liu, Xiaowen Xue, Jianxiang Lin, Shisheng Huang, Wenjie Shu, Xingxu Huang, Zhen Liu, Shengqi Wang, Yunbo Qiao.
      Bacterial double-stranded DNA (dsDNA) cytosine deaminase DddAtox-derived cytosine base editor (DdCBE) and its evolved variant, DddA11, guided by transcription-activator-like effector (TALE) proteins, enable mitochondrial DNA (mtDNA) editing at TC or HC (H = A, C, or T) sequence contexts, while it remains relatively unattainable for GC targets. Here, we identified a dsDNA deaminase originated from a Roseburia intestinalis interbacterial toxin (riDddAtox) and generated CRISPR-mediated nuclear DdCBEs (crDdCBEs) and mitochondrial CBEs (mitoCBEs) using split riDddAtox, which catalyzed C-to-T editing at both HC and GC targets in nuclear and mitochondrial genes. Moreover, transactivator (VP64, P65, or Rta) fusion to the tail of DddAtox- or riDddAtox-mediated crDdCBEs and mitoCBEs substantially improved nuclear and mtDNA editing efficiencies by up to 3.5- and 1.7-fold, respectively. We also used riDddAtox-based and Rta-assisted mitoCBE to efficiently stimulate disease-associated mtDNA mutations in cultured cells and in mouse embryos with conversion frequencies of up to 58% at non-TC targets.
    Keywords:  DdCBE; Roseburia intestinalis; mitoCBE; mitochondrial DNA; mtDNA; non-TC; nuclear DNA; transactivator
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.012
  32. Nat Genet. 2023 May 05.
    Innate immune cell genetic risk factors are linked to COVID-19 severity.
      
    DOI:  https://doi.org/10.1038/s41588-023-01378-y
  33. Nature. 2023 May;617(7960): 227
    Refugee kids find more friends in diverse classrooms.
      
    Keywords:  Human behaviour
    DOI:  https://doi.org/10.1038/d41586-023-01459-2
  34. Science. 2023 May 05. 380(6644): 443
    'Game changer' method lets scientists peer into mice.
    Esra Öz.
      Imaging technique uses standard cell-specific antibodies.
    DOI:  https://doi.org/10.1126/science.adi5368
  35. Nat Commun. 2023 May 04. 14(1): 2567
    Chemical imaging reveals diverse functions of tricarboxylic acid metabolites in root growth and development.
    Tao Zhang, Sarah E Noll, Jesus T Peng, Amman Klair, Abigail Tripka, Nathan Stutzman, Casey Cheng, Richard N Zare, Alexandra J Dickinson.
      Understanding how plants grow is critical for agriculture and fundamental for illuminating principles of multicellular development. Here, we apply desorption electrospray ionization mass spectrometry imaging (DESI-MSI) to the chemical mapping of the developing maize root. This technique reveals a range of small molecule distribution patterns across the gradient of stem cell differentiation in the root. To understand the developmental logic of these patterns, we examine tricarboxylic acid (TCA) cycle metabolites. In both Arabidopsis and maize, we find evidence that elements of the TCA cycle are enriched in developmentally opposing regions. We find that these metabolites, particularly succinate, aconitate, citrate, and α-ketoglutarate, control root development in diverse and distinct ways. Critically, the developmental effects of certain TCA metabolites on stem cell behavior do not correlate with changes in ATP production. These results present insights into development and suggest practical means for controlling plant growth.
    DOI:  https://doi.org/10.1038/s41467-023-38150-z
  36. J Immunol. 2023 May 15. 210(10): 1463-1472
    Deficiencies and Dysregulation of STAT Pathways That Drive Inborn Errors of Immunity: Lessons from Patients and Mouse Models of Disease.
    Kelsey A Toth, Erica G Schmitt, Megan A Cooper.
      The STAT family proteins provide critical signals for immune cell development, differentiation, and proinflammatory and anti-inflammatory responses. Inborn errors of immunity (IEIs) are caused by single gene defects leading to immune deficiency and/or dysregulation, and they have provided opportunities to identify genes important for regulating the human immune response. Studies of patients with IEIs due to altered STAT signaling, and mouse models of these diseases, have helped to shape current understanding of the mechanisms whereby STAT signaling and protein interactions regulate immunity. Although many STAT signaling pathways are shared, clinical and immune phenotypes in patients with monogenic defects of STAT signaling highlight both redundant and nonredundant pathways. In this review, we provide an overview of the shared and unique signaling pathways used by STATs, phenotypes of IEIs with altered STAT signaling, and recent discoveries that have provided insight into the human immune response and treatment of disease.
    DOI:  https://doi.org/10.4049/jimmunol.2200905
  37. Nat Commun. 2023 May 02. 14(1): 2504
    Methionine restriction constrains lipoylation and activates mitochondria for nitrogenic synthesis of amino acids.
    Wen Fang, Liu Jiang, Yibing Zhu, Sen Yang, Hong Qiu, Jiou Cheng, Qingxi Liang, Zong-Cai Tu, Cunqi Ye.
      Methionine restriction (MR) provides metabolic benefits in many organisms. However, mechanisms underlying the MR-induced effect remain incompletely understood. Here, we show in the budding yeast S. cerevisiae that MR relays a signal of S-adenosylmethionine (SAM) deprivation to adapt bioenergetic mitochondria to nitrogenic anabolism. In particular, decreases in cellular SAM constrain lipoate metabolism and protein lipoylation required for the operation of the tricarboxylic acid (TCA) cycle in the mitochondria, leading to incomplete glucose oxidation with an exit of acetyl-CoA and α-ketoglutarate from the TCA cycle to the syntheses of amino acids, such as arginine and leucine. This mitochondrial response achieves a trade-off between energy metabolism and nitrogenic anabolism, which serves as an effector mechanism promoting cell survival under MR.
    DOI:  https://doi.org/10.1038/s41467-023-38289-9
  38. Nat Commun. 2023 May 02. 14(1): 2501
    Gut microbiome dysbiosis across early Parkinson's disease, REM sleep behavior disorder and their first-degree relatives.
    Bei Huang, Steven W H Chau, Yaping Liu, Joey W Y Chan, Jing Wang, Suk Ling Ma, Jihui Zhang, Paul K S Chan, Yun Kit Yeoh, Zigui Chen, Li Zhou, Sunny Hei Wong, Vincent C T Mok, Ka Fai To, Hei Ming Lai, Simon Ng, Claudia Trenkwalder, Francis K L Chan, Yun Kwok Wing.
      The microbiota-gut-brain axis has been suggested to play an important role in Parkinson's disease (PD). Here we performed a cross-sectional study to profile gut microbiota across early PD, REM sleep behavior disorder (RBD), first-degree relatives of RBD (RBD-FDR), and healthy controls, which could reflect the gut-brain staging model of PD. We show gut microbiota compositions are significantly altered in early PD and RBD compared with control and RBD-FDR. Depletion of butyrate-producing bacteria and enrichment of pro-inflammatory Collinsella have already emerged in RBD and RBD-FDR after controlling potential confounders including antidepressants, osmotic laxatives, and bowel movement frequency. Random forest modelling identifies 12 microbial markers that are effective to distinguish RBD from control. These findings suggest that PD-like gut dysbiosis occurs at the prodromal stages of PD when RBD develops and starts to emerge in the younger RBD-FDR subjects. The study will have etiological and diagnostic implications.
    DOI:  https://doi.org/10.1038/s41467-023-38248-4
  39. Sci Adv. 2023 May 05. 9(18): eadd2676
    TMEM106B regulates microglial proliferation and survival in response to demyelination.
    Tingting Zhang, Weilun Pang, Tuancheng Feng, Jennifer Guo, Kenton Wu, Mariela Nunez Santos, Akshayakeerthi Arthanarisami, Alissa L Nana, Quynh Nguyen, Peter J Kim, Joanna L Jankowsky, William W Seeley, Fenghua Hu.
      TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced microglia proliferation and activation and increased microglial apoptosis in response to demyelination. We also found an increase in lysosomal pH and a decrease in lysosomal enzyme activities in TMEM106B-deficient microglia. Furthermore, TMEM106B loss results in a significant decrease in the protein levels of TREM2, an innate immune receptor essential for microglia survival and activation. Specific ablation of TMEM106B in microglia results in similar microglial phenotypes and myelination defects in mice, supporting the idea that microglial TMEM106B is critical for proper microglial activities and myelination. Moreover, the TMEM106B risk allele is associated with myelin loss and decreased microglial numbers in humans. Collectively, our study unveils a previously unknown role of TMEM106B in promoting microglial functionality during demyelination.
    DOI:  https://doi.org/10.1126/sciadv.add2676
  40. Nat Commun. 2023 May 05. 14(1): 2597
    Dynamic and stable hippocampal representations of social identity and reward expectation support associative social memory in male mice.
    Eunji Kong, Kyu-Hee Lee, Jongrok Do, Pilhan Kim, Doyun Lee.
      Recognizing an individual and retrieving and updating the value information assigned to the individual are fundamental abilities for establishing social relationships. To understand the neural mechanisms underlying the association between social identity and reward value, we developed Go-NoGo social discrimination paradigms that required male subject mice to distinguish between familiar mice based on their individually unique characteristics and associate them with reward availability. We found that mice could discriminate individual conspecifics through a brief nose-to-nose investigation, and this ability depended on the dorsal hippocampus. Two-photon calcium imaging revealed that dorsal CA1 hippocampal neurons represented reward expectation during social, but not non-social tasks, and these activities were maintained over days regardless of the identity of the associated mouse. Furthermore, a dynamically changing subset of hippocampal CA1 neurons discriminated between individual mice with high accuracy. Our findings suggest that the neuronal activities in CA1 provide possible neural substrates for associative social memory.
    DOI:  https://doi.org/10.1038/s41467-023-38338-3
  41. Nat Commun. 2023 May 03. 14(1): 2533
    Identification of biomarkers for glycaemic deterioration in type 2 diabetes.
    Roderick C Slieker, Louise A Donnelly, Elina Akalestou, Livia Lopez-Noriega, Rana Melhem, Ayşim Güneş, Frederic Abou Azar, Alexander Efanov, Eleni Georgiadou, Hermine Muniangi-Muhitu, Mahsa Sheikh, Giuseppe N Giordano, Mikael Åkerlund, Emma Ahlqvist, Ashfaq Ali, Karina Banasik, Søren Brunak, Marko Barovic, Gerard A Bouland, Frédéric Burdet, Mickaël Canouil, Iulian Dragan, Petra J M Elders, Celine Fernandez, Andreas Festa, Hugo Fitipaldi, Phillippe Froguel, Valborg Gudmundsdottir, Vilmundur Gudnason, Mathias J Gerl, Amber A van der Heijden, Lori L Jennings, Michael K Hansen, Min Kim, Isabelle Leclerc, Christian Klose, Dmitry Kuznetsov, Dina Mansour Aly, Florence Mehl, Diana Marek, Olle Melander, Anne Niknejad, Filip Ottosson, Imre Pavo, Kevin Duffin, Samreen K Syed, Janice L Shaw, Over Cabrera, Timothy J Pullen, Kai Simons, Michele Solimena, Tommi Suvitaival, Asger Wretlind, Peter Rossing, Valeriya Lyssenko, Cristina Legido Quigley, Leif Groop, Bernard Thorens, Paul W Franks, Gareth E Lim, Jennifer Estall, Mark Ibberson, Joline W J Beulens, Leen M 't Hart, Ewan R Pearson, Guy A Rutter.
      We identify biomarkers for disease progression in three type 2 diabetes cohorts encompassing 2,973 individuals across three molecular classes, metabolites, lipids and proteins. Homocitrulline, isoleucine and 2-aminoadipic acid, eight triacylglycerol species, and lowered sphingomyelin 42:2;2 levels are predictive of faster progression towards insulin requirement. Of ~1,300 proteins examined in two cohorts, levels of GDF15/MIC-1, IL-18Ra, CRELD1, NogoR, FAS, and ENPP7 are associated with faster progression, whilst SMAC/DIABLO, SPOCK1 and HEMK2 predict lower progression rates. In an external replication, proteins and lipids are associated with diabetes incidence and prevalence. NogoR/RTN4R injection improved glucose tolerance in high fat-fed male mice but impaired it in male db/db mice. High NogoR levels led to islet cell apoptosis, and IL-18R antagonised inflammatory IL-18 signalling towards nuclear factor kappa-B in vitro. This comprehensive, multi-disciplinary approach thus identifies biomarkers with potential prognostic utility, provides evidence for possible disease mechanisms, and identifies potential therapeutic avenues to slow diabetes progression.
    DOI:  https://doi.org/10.1038/s41467-023-38148-7
  42. Nat Commun. 2023 04 29. 14(1): 2484
    Reconstruction of the cell pseudo-space from single-cell RNA sequencing data with scSpace.
    Jingyang Qian, Jie Liao, Ziqi Liu, Ying Chi, Yin Fang, Yanrong Zheng, Xin Shao, Bingqi Liu, Yongjin Cui, Wenbo Guo, Yining Hu, Hudong Bao, Penghui Yang, Qian Chen, Mingxiao Li, Bing Zhang, Xiaohui Fan.
      Tissues are highly complicated with spatial heterogeneity in gene expression. However, the cutting-edge single-cell RNA-seq technology eliminates the spatial information of individual cells, which contributes to the characterization of cell identities. Herein, we propose single-cell spatial position associated co-embeddings (scSpace), an integrative method to identify spatially variable cell subpopulations by reconstructing cells onto a pseudo-space with spatial transcriptome references (Visium, STARmap, Slide-seq, etc.). We benchmark scSpace with both simulated and biological datasets, and demonstrate that scSpace can accurately and robustly identify spatially variated cell subpopulations. When employed to reconstruct the spatial architectures of complex tissue such as the brain cortex, the small intestinal villus, the liver lobule, the kidney, the embryonic heart, and others, scSpace shows promising performance on revealing the pairwise cellular spatial association within single-cell data. The application of scSpace in melanoma and COVID-19 exhibits a broad prospect in the discovery of spatial therapeutic markers.
    DOI:  https://doi.org/10.1038/s41467-023-38121-4
  43. Cell Metab. 2023 May 02. pii: S1550-4131(23)00136-5. [Epub ahead of print]35(5): 725-727
    Remote control of autophagy and metabolism in the liver.
    Nektarios Tavernarakis.
      Systemic control of homeostatic processes is of fundamental importance for survival and adaptation in metazoans. In this issue of Cell Metabolism, Chen and colleagues identify and methodically dissect a signaling cascade that is mobilized by the agouti-related peptide (AgRP)-expressing neurons in the hypothalamus, to ultimately modulate autophagy and metabolism in the liver upon starvation.
    DOI:  https://doi.org/10.1016/j.cmet.2023.04.009
  44. Sci Adv. 2023 04 28. 9(17): eabm4945
    The genetic determinants of recurrent somatic mutations in 43,693 blood genomes.
    NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
      Nononcogenic somatic mutations are thought to be uncommon and inconsequential. To test this, we analyzed 43,693 National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine blood whole genomes from 37 cohorts and identified 7131 non-missense somatic mutations that are recurrently mutated in at least 50 individuals. These recurrent non-missense somatic mutations (RNMSMs) are not clearly explained by other clonal phenomena such as clonal hematopoiesis. RNMSM prevalence increased with age, with an average 50-year-old having 27 RNMSMs. Inherited germline variation associated with RNMSM acquisition. These variants were found in genes involved in adaptive immune function, proinflammatory cytokine production, and lymphoid lineage commitment. In addition, the presence of eight specific RNMSMs associated with blood cell traits at effect sizes comparable to Mendelian genetic mutations. Overall, we found that somatic mutations in blood are an unexpectedly common phenomenon with ancestry-specific determinants and human health consequences.
    DOI:  https://doi.org/10.1126/sciadv.abm4945
  45. Nat Med. 2023 May 02.
    Unmasking the elusive erythropoietin-producing 'Norn' cell.
    Amin Abedini, Konstantin A Klötzer, Katalin Susztak.
      
    DOI:  https://doi.org/10.1038/s41591-023-02322-7
  46. Nat Cell Biol. 2023 May 01.
    Lipid droplets and peroxisomes are co-regulated to drive lifespan extension in response to mono-unsaturated fatty acids.
    Katharina Papsdorf, Jason W Miklas, Amir Hosseini, Matias Cabruja, Christopher S Morrow, Marzia Savini, Yong Yu, Carlos G Silva-García, Nicole R Haseley, Luke Meraz Murphy, Pallas Yao, Elisa de Launoit, Scott J Dixon, Michael P Snyder, Meng C Wang, William B Mair, Anne Brunet.
      Dietary mono-unsaturated fatty acids (MUFAs) are linked to longevity in several species. But the mechanisms by which MUFAs extend lifespan remain unclear. Here we show that an organelle network involving lipid droplets and peroxisomes is critical for MUFA-induced longevity in Caenorhabditis elegans. MUFAs upregulate the number of lipid droplets in fat storage tissues. Increased lipid droplet number is necessary for MUFA-induced longevity and predicts remaining lifespan. Lipidomics datasets reveal that MUFAs also modify the ratio of membrane lipids and ether lipids-a signature associated with decreased lipid oxidation. In agreement with this, MUFAs decrease lipid oxidation in middle-aged individuals. Intriguingly, MUFAs upregulate not only lipid droplet number but also peroxisome number. A targeted screen identifies genes involved in the co-regulation of lipid droplets and peroxisomes, and reveals that induction of both organelles is optimal for longevity. Our study uncovers an organelle network involved in lipid homeostasis and lifespan regulation, opening new avenues for interventions to delay aging.
    DOI:  https://doi.org/10.1038/s41556-023-01136-6
  47. Sci Adv. 2023 May 03. 9(18): eadf0115
    Acetylcarnitine shuttling links mitochondrial metabolism to histone acetylation and lipogenesis.
    Luke T Izzo, Sophie Trefely, Christina Demetriadou, Jack M Drummond, Takuya Mizukami, Nina Kuprasertkul, Aimee T Farria, Phuong T T Nguyen, Nivitha Murali, Lauren Reich, Daniel S Kantner, Joshua Shaffer, Hayley Affronti, Alessandro Carrer, Andrew Andrews, Brian C Capell, Nathaniel W Snyder, Kathryn E Wellen.
      The metabolite acetyl-CoA is necessary for both lipid synthesis in the cytosol and histone acetylation in the nucleus. The two canonical precursors to acetyl-CoA in the nuclear-cytoplasmic compartment are citrate and acetate, which are processed to acetyl-CoA by ATP-citrate lyase (ACLY) and acyl-CoA synthetase short-chain 2 (ACSS2), respectively. It is unclear whether other substantial routes to nuclear-cytosolic acetyl-CoA exist. To investigate this, we generated cancer cell lines lacking both ACLY and ACSS2 [double knockout (DKO) cells]. Using stable isotope tracing, we show that both glucose and fatty acids contribute to acetyl-CoA pools and histone acetylation in DKO cells and that acetylcarnitine shuttling can transfer two-carbon units from mitochondria to cytosol. Further, in the absence of ACLY, glucose can feed fatty acid synthesis in a carnitine responsive and carnitine acetyltransferase (CrAT)-dependent manner. The data define acetylcarnitine as an ACLY- and ACSS2-independent precursor to nuclear-cytosolic acetyl-CoA that can support acetylation, fatty acid synthesis, and cell growth.
    DOI:  https://doi.org/10.1126/sciadv.adf0115
  48. Nat Mater. 2023 May;22(5): 532-533
    Unjamming tumour cell invasion through cGAS-STING.
    Matthew Deyell, Samuel F Bakhoum.
      
    DOI:  https://doi.org/10.1038/s41563-023-01542-z
  49. Nature. 2023 May 04.
    New cellular 'organelle' discovered inside fruit-fly intestines.
    Gemma Conroy.
      
    Keywords:  Cell biology; Imaging; Structural biology
    DOI:  https://doi.org/10.1038/d41586-023-01518-8
  50. Cell. 2023 Apr 28. pii: S0092-8674(23)00414-2. [Epub ahead of print]
    Plasma membrane preassociation drives β-arrestin coupling to receptors and activation.
    Jak Grimes, Zsombor Koszegi, Yann Lanoiselée, Tamara Miljus, Shannon L O'Brien, Tomasz M Stepniewski, Brian Medel-Lacruz, Mithu Baidya, Maria Makarova, Ravi Mistry, Joëlle Goulding, Julia Drube, Carsten Hoffmann, Dylan M Owen, Arun K Shukla, Jana Selent, Stephen J Hill, Davide Calebiro.
      β-arrestin plays a key role in G protein-coupled receptor (GPCR) signaling and desensitization. Despite recent structural advances, the mechanisms that govern receptor-β-arrestin interactions at the plasma membrane of living cells remain elusive. Here, we combine single-molecule microscopy with molecular dynamics simulations to dissect the complex sequence of events involved in β-arrestin interactions with both receptors and the lipid bilayer. Unexpectedly, our results reveal that β-arrestin spontaneously inserts into the lipid bilayer and transiently interacts with receptors via lateral diffusion on the plasma membrane. Moreover, they indicate that, following receptor interaction, the plasma membrane stabilizes β-arrestin in a longer-lived, membrane-bound state, allowing it to diffuse to clathrin-coated pits separately from the activating receptor. These results expand our current understanding of β-arrestin function at the plasma membrane, revealing a critical role for β-arrestin preassociation with the lipid bilayer in facilitating its interactions with receptors and subsequent activation.
    Keywords:  G protein-coupled receptors; GPCR; TIRF; arrestin; plasma membrane; protein-protein interactions; single-molecule microscopy
    DOI:  https://doi.org/10.1016/j.cell.2023.04.018
  51. Commun Biol. 2023 May 04. 6(1): 484
    Morphodynamical cell state description via live-cell imaging trajectory embedding.
    Jeremy Copperman, Sean M Gross, Young Hwan Chang, Laura M Heiser, Daniel M Zuckerman.
      Time-lapse imaging is a powerful approach to gain insight into the dynamic responses of cells, but the quantitative analysis of morphological changes over time remains challenging. Here, we exploit the concept of "trajectory embedding" to analyze cellular behavior using morphological feature trajectory histories-that is, multiple time points simultaneously, rather than the more common practice of examining morphological feature time courses in single timepoint (snapshot) morphological features. We apply this approach to analyze live-cell images of MCF10A mammary epithelial cells after treatment with a panel of microenvironmental perturbagens that strongly modulate cell motility, morphology, and cell cycle behavior. Our morphodynamical trajectory embedding analysis constructs a shared cell state landscape revealing ligand-specific regulation of cell state transitions and enables quantitative and descriptive models of single-cell trajectories. Additionally, we show that incorporation of trajectories into single-cell morphological analysis enables (i) systematic characterization of cell state trajectories, (ii) better separation of phenotypes, and (iii) more descriptive models of ligand-induced differences as compared to snapshot-based analysis. This morphodynamical trajectory embedding is broadly applicable to the quantitative analysis of cell responses via live-cell imaging across many biological and biomedical applications.
    DOI:  https://doi.org/10.1038/s42003-023-04837-8
  52. Sci Adv. 2023 May 03. 9(18): eadf7737
    Divergent acute versus prolonged pharmacological GLP-1R responses in adult β cell-specific β-arrestin 2 knockout mice.
    Stavroula Bitsi, Liliane El Eid, Yusman Manchanda, Affiong I Oqua, Nimco Mohamed, Ben Hansen, Kinga Suba, Guy A Rutter, Victoria Salem, Ben Jones, Alejandra Tomas.
      The glucagon-like peptide-1 receptor (GLP-1R) is a major type 2 diabetes therapeutic target. Stimulated GLP-1Rs are rapidly desensitized by β-arrestins, scaffolding proteins that not only terminate G protein interactions but also act as independent signaling mediators. Here, we have assessed in vivo glycemic responses to the pharmacological GLP-1R agonist exendin-4 in adult β cell-specific β-arrestin 2 knockout (KO) mice. KOs displayed a sex-dimorphic phenotype consisting of weaker acute responses that improved 6 hours after agonist injection. Similar effects were observed for semaglutide and tirzepatide but not with biased agonist exendin-phe1. Acute cyclic adenosine 5'-monophosphate increases were impaired, but desensitization reduced in KO islets. The former defect was attributed to enhanced β-arrestin 1 and phosphodiesterase 4 activities, while reduced desensitization co-occurred with impaired GLP-1R recycling and lysosomal targeting, increased trans-Golgi network signaling, and reduced GLP-1R ubiquitination. This study has unveiled fundamental aspects of GLP-1R response regulation with direct application to the rational design of GLP-1R-targeting therapeutics.
    DOI:  https://doi.org/10.1126/sciadv.adf7737
  53. Nature. 2023 May 03.
    Structure of the most abundant human gut virus.
      
    Keywords:  Microbiology; Structural biology; Virology
    DOI:  https://doi.org/10.1038/d41586-023-01336-y
  54. Proc Natl Acad Sci U S A. 2023 May 09. 120(19): e2213696120
    A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
    Yasuhide Kuwabara, Allen J York, Suh-Chin Lin, Michelle A Sargent, Kelly M Grimes, James P Pirruccello, Jeffery D Molkentin.
      To better understand the genetic basis of heart disease, we identified a variant in the Flightless-I homolog (FLII) gene that generates a R1243H missense change and predisposes to cardiac remodeling across multiple previous human genome-wide association studies (GWAS). Since this gene is of unknown function in the mammalian heart we generated gain- and loss-of-function genetically altered mice, as well as knock-in mice with the syntenic R1245H amino acid substitution, which showed that Flii protein binds the sarcomeric actin thin filament and influences its length. Deletion of Flii from the heart, or mice with the R1245H amino acid substitution, show cardiomyopathy due to shortening of the actin thin filaments. Mechanistically, Flii is a known actin binding protein that we show associates with tropomodulin-1 (TMOD1) to regulate sarcomere thin filament length. Indeed, overexpression of leiomodin-2 in the heart, which lengthens the actin-containing thin filaments, partially rescued disease due to heart-specific deletion of Flii. Collectively, the identified FLII human variant likely increases cardiomyopathy risk through an alteration in sarcomere structure and associated contractile dynamics, like other sarcomere gene-based familial cardiomyopathies.
    Keywords:  actin thin filament; cardiomyopathy; heart; sarcomere
    DOI:  https://doi.org/10.1073/pnas.2213696120
  55. Sci Adv. 2023 04 28. 9(17): eadf6205
    Coupling of protein condensates to ordered lipid domains determines functional membrane organization.
    Hong-Yin Wang, Sze Ham Chan, Simli Dey, Ivan Castello-Serrano, Michael K Rosen, Jonathon A Ditlev, Kandice R Levental, Ilya Levental.
      During T cell activation, the transmembrane adaptor protein LAT (linker for activation of T cells) forms biomolecular condensates with Grb2 and Sos1, facilitating signaling. LAT has also been associated with cholesterol-rich condensed lipid domains; However, the potential coupling between protein condensation and lipid phase separation and its role in organizing T cell signaling were unknown. Here, we report that LAT/Grb2/Sos1 condensates reconstituted on model membranes can induce and template lipid domains, indicating strong coupling between lipid- and protein-based phase separation. Correspondingly, activation of T cells induces cytoplasmic protein condensates that associate with and stabilize raft-like membrane domains. Inversely, lipid domains nucleate and stabilize LAT protein condensates in both reconstituted and living systems. This coupling of lipid and protein assembly is functionally important, as uncoupling of lipid domains from cytoplasmic protein condensates abrogates T cell activation. Thus, thermodynamic coupling between protein condensates and ordered lipid domains regulates the functional organization of living membranes.
    DOI:  https://doi.org/10.1126/sciadv.adf6205
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