bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–07–23
47 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. EGR2 drives TH17 cell pathogenicity in autoimmune neuroinflammation.
  2. H3K36 methylation maintains cell identity by regulating opposing lineage programmes.
  3. Finding my postdoc identity.
  4. Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction.
  5. Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry.
  6. IKK2/NFkB signaling controls lung resident CD8+ T cell memory during influenza infection.
  7. A GPCR checkpoint drives CD8+ T cell dysfunction and immunotherapy failure in mice.
  8. Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.
  9. Organization of the human intestine at single-cell resolution.
  10. Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium.
  11. UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.
  12. ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription.
  13. Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire.
  14. An open resource combining multi-contrast MRI and microscopy in the macaque brain.
  15. Innate immune sensing by cGAS-STING in animals reveals unexpected messengers.
  16. Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons.
  17. A spatially resolved timeline of the human maternal-fetal interface.
  18. Highly specific and non-invasive imaging of Piezo1-dependent activity across scales using GenEPi.
  19. Editorial Expression of Concern.
  20. Enhancing bacteriophage therapeutics through in situ production and release of heterologous antimicrobial effectors.
  21. Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel.
  22. Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin.
  23. Comprehensive analysis of intercellular communication in the thermogenic adipose niche.
  24. Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure.
  25. ThPOK is a critical multifaceted regulator of myeloid lineage development.
  26. Dual-color DNA-PAINT single-particle tracking enables extended studies of membrane protein interactions.
  27. Identification of ligand-receptor pairs that drive human astrocyte development.
  28. Formation of bronchus-associated lymphoid tissue (BALT) for early life immune protection.
  29. Advances and prospects for the Human BioMolecular Atlas Program (HuBMAP).
  30. Epigenetic mechanisms to propagate histone acetylation by p300/CBP.
  31. Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation.
  32. Slingshot homolog-1-mediated Nrf2 sequestration tips the balance from neuroprotection to neurodegeneration in Alzheimer's disease.
  33. Thousands of cGAS-like receptors described in animals.
  34. Preserving mitochondria to treat hypertrophic cardiomyopathy: From rare mitochondrial DNA mutation to heart failure therapy?
  35. A cell-type-specific error-correction signal in the posterior parietal cortex.
  36. Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction.
  37. Prostaglandin E2 activates melanin-concentrating hormone neurons to drive diet-induced obesity.
  38. T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity.
  39. Dementia risk linked to blood-protein imbalance in middle age.
  40. Orphan quality control shapes network dynamics and gene expression.
  41. Heart failure causes sleepless nights.
  42. CellSighter: a neural network to classify cells in highly multiplexed images.
  43. IL-1β turnover by the UBE2L3 ubiquitin conjugating enzyme and HECT E3 ligases limits inflammation.
  44. LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits.
  45. Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons.
  46. Transcriptomes of human primary skin fibroblasts of healthy individuals reveal age-associated mRNAs and long noncoding RNAs.
  47. Nutritional redundancy in the human diet and its application in phenotype association studies.
  1. Nat Immunol. 2023 Jul 20.
    EGR2 drives TH17 cell pathogenicity in autoimmune neuroinflammation.
      
    DOI:  https://doi.org/10.1038/s41590-023-01568-0
  2. Nat Cell Biol. 2023 Jul 17.
    H3K36 methylation maintains cell identity by regulating opposing lineage programmes.
    Michael S Hoetker, Masaki Yagi, Bruno Di Stefano, Justin Langerman, Simona Cristea, Lai Ping Wong, Aaron J Huebner, Jocelyn Charlton, Weixian Deng, Chuck Haggerty, Ruslan I Sadreyev, Alexander Meissner, Franziska Michor, Kathrin Plath, Konrad Hochedlinger.
      The epigenetic mechanisms that maintain differentiated cell states remain incompletely understood. Here we employed histone mutants to uncover a crucial role for H3K36 methylation in the maintenance of cell identities across diverse developmental contexts. Focusing on the experimental induction of pluripotency, we show that H3K36M-mediated depletion of H3K36 methylation endows fibroblasts with a plastic state poised to acquire pluripotency in nearly all cells. At a cellular level, H3K36M facilitates epithelial plasticity by rendering fibroblasts insensitive to TGFβ signals. At a molecular level, H3K36M enables the decommissioning of mesenchymal enhancers and the parallel activation of epithelial/stem cell enhancers. This enhancer rewiring is Tet dependent and redirects Sox2 from promiscuous somatic to pluripotency targets. Our findings reveal a previously unappreciated dual role for H3K36 methylation in the maintenance of cell identity by integrating a crucial developmental pathway into sustained expression of cell-type-specific programmes, and by opposing the expression of alternative lineage programmes through enhancer methylation.
    DOI:  https://doi.org/10.1038/s41556-023-01191-z
  3. Science. 2023 Jul 21. 381(6655): 350
    Finding my postdoc identity.
    Moamen Elmassry.
      
    DOI:  https://doi.org/10.1126/science.adj7670
  4. Nat Commun. 2023 07 19. 14(1): 4356
    Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction.
    Luis Rios, Suman Pokhrel, Sin-Jin Li, Gwangbeom Heo, Bereketeab Haileselassie, Daria Mochly-Rosen.
      The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to mitochondrial Fis1 and subsequently, mitochondrial fragmentation, ROS production, metabolic collapse, and cell death. Because Drp1 also mediates physiological fission by binding to mitochondrial Mff, therapeutics that inhibit pathological fission should spare physiological mitochondrial fission. P110, a peptide inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models of neurodegeneration, ischemia, and sepsis without blocking the physiological functions of Drp1. Since peptides have pharmacokinetic limitations, we set out to identify small molecules that mimic P110's benefit. We map the P110-binding site to a switch I-adjacent grove (SWAG) on Drp1. Screening for SWAG-binding small molecules identifies SC9, which mimics P110's benefits in cells and a mouse model of endotoxemia. We suggest that the SWAG-binding small molecules discovered in this study may reduce the burden of Drp1-mediated pathologies and potentially pathologies associated with other members of the GTPase family.
    DOI:  https://doi.org/10.1038/s41467-023-40043-0
  5. Nat Commun. 2023 Jul 20. 14(1): 4368
    Antiviral HIV-1 SERINC restriction factors disrupt virus membrane asymmetry.
    Susan A Leonhardt, Michael D Purdy, Jonathan R Grover, Ziwei Yang, Sandra Poulos, William E McIntire, Elizabeth A Tatham, Satchal K Erramilli, Kamil Nosol, Kin Kui Lai, Shilei Ding, Maolin Lu, Pradeep D Uchil, Andrés Finzi, Alan Rein, Anthony A Kossiakoff, Walther Mothes, Mark Yeager.
      The host proteins SERINC3 and SERINC5 are HIV-1 restriction factors that reduce infectivity when incorporated into the viral envelope. The HIV-1 accessory protein Nef abrogates incorporation of SERINCs via binding to intracellular loop 4 (ICL4). Here, we determine cryoEM maps of full-length human SERINC3 and an ICL4 deletion construct, which reveal that hSERINC3 is comprised of two α-helical bundles connected by a ~ 40-residue, highly tilted, "crossmember" helix. The design resembles non-ATP-dependent lipid transporters. Consistently, purified hSERINCs reconstituted into proteoliposomes induce flipping of phosphatidylserine (PS), phosphatidylethanolamine and phosphatidylcholine. Furthermore, SERINC3, SERINC5 and the scramblase TMEM16F expose PS on the surface of HIV-1 and reduce infectivity, with similar results in MLV. SERINC effects in HIV-1 and MLV are counteracted by Nef and GlycoGag, respectively. Our results demonstrate that SERINCs are membrane transporters that flip lipids, resulting in a loss of membrane asymmetry that is strongly correlated with changes in Env conformation and loss of infectivity.
    DOI:  https://doi.org/10.1038/s41467-023-39262-2
  6. Nat Commun. 2023 07 19. 14(1): 4331
    IKK2/NFkB signaling controls lung resident CD8+ T cell memory during influenza infection.
    Curtis J Pritzl, Dezzarae Luera, Karin M Knudson, Michael J Quaney, Michael J Calcutt, Mark A Daniels, Emma Teixeiro.
      CD8+ T cell tissue resident memory (TRM) cells are especially suited to control pathogen spread at mucosal sites. However, their maintenance in lung is short-lived. TCR-dependent NFkB signaling is crucial for T cell memory but how and when NFkB signaling modulates tissue resident and circulating T cell memory during the immune response is unknown. Here, we find that enhancing NFkB signaling in T cells once memory to influenza is established, increases pro-survival Bcl-2 and CD122 levels thus boosting lung CD8+ TRM maintenance. By contrast, enhancing NFkB signals during the contraction phase of the response leads to a defect in CD8+ TRM differentiation without impairing recirculating memory subsets. Specifically, inducible activation of NFkB via constitutive active IKK2 or TNF interferes with TGFβ signaling, resulting in defects of lung CD8+ TRM imprinting molecules CD69, CD103, Runx3 and Eomes. Conversely, inhibiting NFkB signals not only recovers but improves the transcriptional signature and generation of lung CD8+ TRM. Thus, NFkB signaling is a critical regulator of tissue resident memory, whose levels can be tuned at specific times during infection to boost lung CD8+ TRM.
    DOI:  https://doi.org/10.1038/s41467-023-40107-1
  7. Nat Immunol. 2023 Jul 17.
    A GPCR checkpoint drives CD8+ T cell dysfunction and immunotherapy failure in mice.
      
    DOI:  https://doi.org/10.1038/s41590-023-01567-1
  8. Cell Metab. 2023 Jul 14. pii: S1550-4131(23)00225-5. [Epub ahead of print]
    Liver mitochondrial cristae organizing protein MIC19 promotes energy expenditure and pedestrian locomotion by altering nucleotide metabolism.
    Jee Hyung Sohn, Beste Mutlu, Pedro Latorre-Muro, Jiaxin Liang, Christopher F Bennett, Kfir Sharabi, Noa Kantorovich, Mark Jedrychowski, Steven P Gygi, Alexander S Banks, Pere Puigserver.
      Liver mitochondria undergo architectural remodeling that maintains energy homeostasis in response to feeding and fasting. However, the specific components and molecular mechanisms driving these changes and their impact on energy metabolism remain unclear. Through comparative mouse proteomics, we found that fasting induces strain-specific mitochondrial cristae formation in the liver by upregulating MIC19, a subunit of the MICOS complex. Enforced MIC19 expression in the liver promotes cristae formation, mitochondrial respiration, and fatty acid oxidation while suppressing gluconeogenesis. Mice overexpressing hepatic MIC19 show resistance to diet-induced obesity and improved glucose homeostasis. Interestingly, MIC19 overexpressing mice exhibit elevated energy expenditure and increased pedestrian locomotion. Metabolite profiling revealed that uracil accumulates in the livers of these mice due to increased uridine phosphorylase UPP2 activity. Furthermore, uracil-supplemented diet increases locomotion in wild-type mice. Thus, MIC19-induced mitochondrial cristae formation in the liver increases uracil as a signal to promote locomotion, with protective effects against diet-induced obesity.
    Keywords:  brisk walking; diabetes; fatty liver; mitochondrial cristae; obesity; uracil
    DOI:  https://doi.org/10.1016/j.cmet.2023.06.015
  9. Nature. 2023 Jul;619(7970): 572-584
    Organization of the human intestine at single-cell resolution.
    John W Hickey, Winston R Becker, Stephanie A Nevins, Aaron Horning, Almudena Espin Perez, Chenchen Zhu, Bokai Zhu, Bei Wei, Roxanne Chiu, Derek C Chen, Daniel L Cotter, Edward D Esplin, Annika K Weimer, Chiara Caraccio, Vishal Venkataraaman, Christian M Schürch, Sarah Black, Maria Brbić, Kaidi Cao, Shuxiao Chen, Weiruo Zhang, Emma Monte, Nancy R Zhang, Zongming Ma, Jure Leskovec, Zhengyan Zhang, Shin Lin, Teri Longacre, Sylvia K Plevritis, Yiing Lin, Garry P Nolan, William J Greenleaf, Michael Snyder.
      The intestine is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota and affects overall health1. The intesting has a length of over nine metres, along which there are differences in structure and function2. The localization of individual cell types, cell type development trajectories and detailed cell transcriptional programs probably drive these differences in function. Here, to better understand these differences, we evaluated the organization of single cells using multiplexed imaging and single-nucleus RNA and open chromatin assays across eight different intestinal sites from nine donors. Through systematic analyses, we find cell compositions that differ substantially across regions of the intestine and demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighbourhoods and communities, highlighting distinct immunological niches that are present in the intestine. We also map gene regulatory differences in these cells that are suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation and organization for this organ, and serve as an important reference map for understanding human biology and disease.
    DOI:  https://doi.org/10.1038/s41586-023-05915-x
  10. Nat Cell Biol. 2023 Jul 17.
    Haematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic endothelium.
    Joey J Ghersi, Gabriel Baldissera, Jared Hintzen, Stephanie A Luff, Siyuan Cheng, Ivan Fan Xia, Christopher M Sturgeon, Stefania Nicoli.
      Definitive haematopoietic stem and progenitor cells (HSPCs) generate erythroid, lymphoid and myeloid lineages. HSPCs are produced in the embryo via transdifferentiation of haemogenic endothelial cells in the aorta-gonad-mesonephros (AGM). HSPCs in the AGM are heterogeneous in differentiation and proliferative output, but how these intrinsic differences are acquired remains unanswered. Here we discovered that loss of microRNA (miR)-128 in zebrafish leads to an expansion of HSPCs in the AGM with different cell cycle states and a skew towards erythroid and lymphoid progenitors. Manipulating miR-128 in differentiating haemogenic endothelial cells, before their transition to HSPCs, recapitulated the lineage skewing in both zebrafish and human pluripotent stem cells. miR-128 promotes Wnt and Notch signalling in the AGM via post-transcriptional repression of the Wnt inhibitor csnk1a1 and the Notch ligand jag1b. De-repression of cskn1a1 resulted in replicative and erythroid-biased HSPCs, whereas de-repression of jag1b resulted in G2/M and lymphoid-biased HSPCs with long-term consequence on the respective blood lineages. We propose that HSPC heterogeneity arises in the AGM endothelium and is programmed in part by Wnt and Notch signalling.
    DOI:  https://doi.org/10.1038/s41556-023-01187-9
  11. Mol Cell. 2023 Jul 12. pii: S1097-2765(23)00475-6. [Epub ahead of print]
    UBR5 forms ligand-dependent complexes on chromatin to regulate nuclear hormone receptor stability.
    Jonathan M Tsai, Jacob D Aguirre, Yen-Der Li, Jared Brown, Vivian Focht, Lukas Kater, Georg Kempf, Brittany Sandoval, Stefan Schmitt, Justine C Rutter, Pius Galli, Colby R Sandate, Jevon A Cutler, Charles Zou, Katherine A Donovan, Ryan J Lumpkin, Simone Cavadini, Paul M C Park, Quinlan Sievers, Charlie Hatton, Elizabeth Ener, Brandon D Regalado, Micah T Sperling, Mikołaj Słabicki, Jeonghyeon Kim, Rebecca Zon, Zinan Zhang, Peter G Miller, Roger Belizaire, Adam S Sperling, Eric S Fischer, Rafael Irizarry, Scott A Armstrong, Nicolas H Thomä, Benjamin L Ebert.
      Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Agonist binding triggers NR activation and subsequent degradation by unknown ligand-dependent ubiquitin ligase machinery. NR degradation is critical for therapeutic efficacy in malignancies that are driven by retinoic acid and estrogen receptors. Here, we demonstrate the ubiquitin ligase UBR5 drives degradation of multiple agonist-bound NRs, including the retinoic acid receptor alpha (RARA), retinoid x receptor alpha (RXRA), glucocorticoid, estrogen, liver-X, progesterone, and vitamin D receptors. We present the high-resolution cryo-EMstructure of full-length human UBR5 and a negative stain model representing its interaction with RARA/RXRA. Agonist ligands induce sequential, mutually exclusive recruitment of nuclear coactivators (NCOAs) and UBR5 to chromatin to regulate transcriptional networks. Other pharmacological ligands such as selective estrogen receptor degraders (SERDs) degrade their receptors through differential recruitment of UBR5 or RNF111. We establish the UBR5 transcriptional regulatory hub as a common mediator and regulator of NR-induced transcription.
    Keywords:  HECT-E3 ligases; nuclear receptors; protein degradation; structural biology; ubiquitin ligases
    DOI:  https://doi.org/10.1016/j.molcel.2023.06.028
  12. Nat Cell Biol. 2023 Jul 17.
    ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription.
    Chuan-Yang Dai, Chai Chee Ng, Grace Ching Ching Hung, Ina Kirmes, Laetitia A Hughes, Yunguang Du, Christopher A Brosnan, Arnaud Ahier, Anne Hahn, Cole M Haynes, Oliver Rackham, Aleksandra Filipovska, Steven Zuryn.
      The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome (mtDNA) requires separate enzymatic activities that can sterically compete1, suggesting a life-long trade-off between these two processes. Here in Caenorhabditis elegans, we find that the bZIP transcription factor ATFS-1/Atf5 (refs. 2,3) regulates this balance in favour of mtDNA repair by localizing to mitochondria and interfering with the assembly of the mitochondrial pre-initiation transcription complex between HMG-5/TFAM and RPOM-1/mtRNAP. ATFS-1-mediated transcriptional inhibition decreases age-dependent mtDNA molecular damage through the DNA glycosylase NTH-1/NTH1, as well as the helicase TWNK-1/TWNK, resulting in an enhancement in the functional longevity of cells and protection against decline in animal behaviour caused by targeted and severe mtDNA damage. Together, our findings reveal that ATFS-1 acts as a molecular focal point for the control of balance between genome expression and maintenance in the mitochondria.
    DOI:  https://doi.org/10.1038/s41556-023-01192-y
  13. Nat Commun. 2023 Jul 21. 14(1): 4419
    Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire.
    Oscar L Rodriguez, Yana Safonova, Catherine A Silver, Kaitlyn Shields, William S Gibson, Justin T Kos, David Tieri, Hanzhong Ke, Katherine J L Jackson, Scott D Boyd, Melissa L Smith, Wayne A Marasco, Corey T Watson.
      Variation in the antibody response has been linked to differential outcomes in disease, and suboptimal vaccine and therapeutic responsiveness, the determinants of which have not been fully elucidated. Countering models that presume antibodies are generated largely by stochastic processes, we demonstrate that polymorphisms within the immunoglobulin heavy chain locus (IGH) impact the naive and antigen-experienced antibody repertoire, indicating that genetics predisposes individuals to mount qualitatively and quantitatively different antibody responses. We pair recently developed long-read genomic sequencing methods with antibody repertoire profiling to comprehensively resolve IGH genetic variation, including novel structural variants, single nucleotide variants, and genes and alleles. We show that IGH germline variants determine the presence and frequency of antibody genes in the expressed repertoire, including those enriched in functional elements linked to V(D)J recombination, and overlapping disease-associated variants. These results illuminate the power of leveraging IGH genetics to better understand the regulation, function, and dynamics of the antibody response in disease.
    DOI:  https://doi.org/10.1038/s41467-023-40070-x
  14. Nat Commun. 2023 07 19. 14(1): 4320
    An open resource combining multi-contrast MRI and microscopy in the macaque brain.
    Amy F D Howard, Istvan N Huszar, Adele Smart, Michiel Cottaar, Greg Daubney, Taylor Hanayik, Alexandre A Khrapitchev, Rogier B Mars, Jeroen Mollink, Connor Scott, Nicola R Sibson, Jerome Sallet, Saad Jbabdi, Karla L Miller.
      Understanding brain structure and function often requires combining data across different modalities and scales to link microscale cellular structures to macroscale features of whole brain organisation. Here we introduce the BigMac dataset, a resource combining in vivo MRI, extensive postmortem MRI and multi-contrast microscopy for multimodal characterisation of a single whole macaque brain. The data spans modalities (MRI and microscopy), tissue states (in vivo and postmortem), and four orders of spatial magnitude, from microscopy images with micrometre or sub-micrometre resolution, to MRI signals on the order of millimetres. Crucially, the MRI and microscopy images are carefully co-registered together to facilitate quantitative multimodal analyses. Here we detail the acquisition, curation, and first release of the data, that together make BigMac a unique, openly-disseminated resource available to researchers worldwide. Further, we demonstrate example analyses and opportunities afforded by the data, including improvement of connectivity estimates from ultra-high angular resolution diffusion MRI, neuroanatomical insight provided by polarised light imaging and myelin-stained histology, and the joint analysis of MRI and microscopy data for reconstruction of the microscopy-inspired connectome. All data and code are made openly available.
    DOI:  https://doi.org/10.1038/s41467-023-39916-1
  15. Cell. 2023 Jul 20. pii: S0092-8674(23)00690-6. [Epub ahead of print]186(15): 3145-3147
    Innate immune sensing by cGAS-STING in animals reveals unexpected messengers.
    Leonie Unterholzner.
      The DNA sensor cGAS and its adaptor STING constitute an ancient pathogen detection mechanism, but it is unclear to what extent its function is conserved across the animal kingdom. In this issue of Cell, Kranzusch and colleagues identify thousands of cGAS-like receptors and discover networks of second messengers that activate innate immune responses in animals.
    DOI:  https://doi.org/10.1016/j.cell.2023.06.014
  16. Nat Commun. 2023 07 19. 14(1): 4321
    Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons.
    Seul Ki Kim, Le Trung Tran, Cherl NamKoong, Hyung Jin Choi, Hye Jin Chun, Yong-Ho Lee, MyungHyun Cheon, ChiHye Chung, Junmo Hwang, Hyun-Ho Lim, Dong Min Shin, Yun-Hee Choi, Ki Woo Kim.
      Small humanin-like peptide 2 (SHLP2) is a mitochondrial-derived peptide implicated in several biological processes such as aging and oxidative stress. However, its functional role in the regulation of energy homeostasis remains unclear, and its corresponding receptor is not identified. Hereby, we demonstrate that both systemic and intracerebroventricular (ICV) administrations of SHLP2 protected the male mice from high-fat diet (HFD)-induced obesity and improved insulin sensitivity. In addition, the activation of pro-opiomelanocortin (POMC) neurons by SHLP2 in the arcuate nucleus of the hypothalamus (ARC) is involved in the suppression of food intake and the promotion of thermogenesis. Through high-throughput structural complementation screening, we discovered that SHLP2 binds to and activates chemokine receptor 7 (CXCR7). Taken together, our study not only reveals the therapeutic potential of SHLP2 in metabolic disorders but also provides important mechanistic insights into how it exerts its effects on energy homeostasis.
    DOI:  https://doi.org/10.1038/s41467-023-40082-7
  17. Nature. 2023 Jul;619(7970): 595-605
    A spatially resolved timeline of the human maternal-fetal interface.
    Shirley Greenbaum, Inna Averbukh, Erin Soon, Gabrielle Rizzuto, Alex Baranski, Noah F Greenwald, Adam Kagel, Marc Bosse, Eleni G Jaswa, Zumana Khair, Shirley Kwok, Shiri Warshawsky, Hadeesha Piyadasa, Mako Goldston, Angie Spence, Geneva Miller, Morgan Schwartz, Will Graf, David Van Valen, Virginia D Winn, Travis Hollmann, Leeat Keren, Matt van de Rijn, Michael Angelo.
      Beginning in the first trimester, fetally derived extravillous trophoblasts (EVTs) invade the uterus and remodel its spiral arteries, transforming them into large, dilated blood vessels. Several mechanisms have been proposed to explain how EVTs coordinate with the maternal decidua to promote a tissue microenvironment conducive to spiral artery remodelling (SAR)1-3. However, it remains a matter of debate regarding which immune and stromal cells participate in these interactions and how this evolves with respect to gestational age. Here we used a multiomics approach, combining the strengths of spatial proteomics and transcriptomics, to construct a spatiotemporal atlas of the human maternal-fetal interface in the first half of pregnancy. We used multiplexed ion beam imaging by time-of-flight and a 37-plex antibody panel to analyse around 500,000 cells and 588 arteries within intact decidua from 66 individuals between 6 and 20 weeks of gestation, integrating this dataset with co-registered transcriptomics profiles. Gestational age substantially influenced the frequency of maternal immune and stromal cells, with tolerogenic subsets expressing CD206, CD163, TIM-3, galectin-9 and IDO-1 becoming increasingly enriched and colocalized at later time points. By contrast, SAR progression preferentially correlated with EVT invasion and was transcriptionally defined by 78 gene ontology pathways exhibiting distinct monotonic and biphasic trends. Last, we developed an integrated model of SAR whereby invasion is accompanied by the upregulation of pro-angiogenic, immunoregulatory EVT programmes that promote interactions with the vascular endothelium while avoiding the activation of maternal immune cells.
    DOI:  https://doi.org/10.1038/s41586-023-06298-9
  18. Nat Commun. 2023 07 19. 14(1): 4352
    Highly specific and non-invasive imaging of Piezo1-dependent activity across scales using GenEPi.
    Sine Yaganoglu, Konstantinos Kalyviotis, Christina Vagena-Pantoula, Dörthe Jülich, Benjamin M Gaub, Maaike Welling, Tatiana Lopes, Dariusz Lachowski, See Swee Tang, Armando Del Rio Hernandez, Victoria Salem, Daniel J Müller, Scott A Holley, Julien Vermot, Jian Shi, Nordine Helassa, Katalin Török, Periklis Pantazis.
      Mechanosensing is a ubiquitous process to translate external mechanical stimuli into biological responses. Piezo1 ion channels are directly gated by mechanical forces and play an essential role in cellular mechanotransduction. However, readouts of Piezo1 activity are mainly examined by invasive or indirect techniques, such as electrophysiological analyses and cytosolic calcium imaging. Here, we introduce GenEPi, a genetically-encoded fluorescent reporter for non-invasive optical monitoring of Piezo1-dependent activity. We demonstrate that GenEPi has high spatiotemporal resolution for Piezo1-dependent stimuli from the single-cell level to that of the entire organism. GenEPi reveals transient, local mechanical stimuli in the plasma membrane of single cells, resolves repetitive contraction-triggered stimulation of beating cardiomyocytes within microtissues, and allows for robust and reliable monitoring of Piezo1-dependent activity in vivo. GenEPi will enable non-invasive optical monitoring of Piezo1 activity in mechanochemical feedback loops during development, homeostatic regulation, and disease.
    DOI:  https://doi.org/10.1038/s41467-023-40134-y
  19. Sci Adv. 2023 Jul 21. 9(29): eabh0587
    Editorial Expression of Concern.
    H Holden Thorp.
      
    DOI:  https://doi.org/10.1126/sciadv.adj8941
  20. Nat Commun. 2023 Jul 20. 14(1): 4337
    Enhancing bacteriophage therapeutics through in situ production and release of heterologous antimicrobial effectors.
    Jiemin Du, Susanne Meile, Jasmin Baggenstos, Tobias Jäggi, Pietro Piffaretti, Laura Hunold, Cassandra I Matter, Lorenz Leitner, Thomas M Kessler, Martin J Loessner, Samuel Kilcher, Matthew Dunne.
      Bacteriophages operate via pathogen-specific mechanisms of action distinct from conventional, broad-spectrum antibiotics and are emerging as promising alternative antimicrobials. However, phage-mediated killing is often limited by bacterial resistance development. Here, we engineer phages for target-specific effector gene delivery and host-dependent production of colicin-like bacteriocins and cell wall hydrolases. Using urinary tract infection (UTI) as a model, we show how heterologous effector phage therapeutics (HEPTs) suppress resistance and improve uropathogen killing by dual phage- and effector-mediated targeting. Moreover, we designed HEPTs to control polymicrobial uropathogen communities through production of effectors with cross-genus activity. Using phage-based companion diagnostics, we identified potential HEPT responder patients and treated their urine ex vivo. Compared to wildtype phage, a colicin E7-producing HEPT demonstrated superior control of patient E. coli bacteriuria. Arming phages with heterologous effectors paves the way for successful UTI treatment and represents a versatile tool to enhance and adapt phage-based precision antimicrobials.
    DOI:  https://doi.org/10.1038/s41467-023-39612-0
  21. Nat Commun. 2023 07 18. 14(1): 4284
    Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel.
    Zhengshan Hu, Xiangdong Zheng, Jian Yang.
      Cyclic nucleotide-gated (CNG) channels transduce chemical signals into electrical signals in sensory receptors and neurons. They are activated by cGMP or cAMP, which bind to the cyclic nucleotide-binding domain (CNBD) to open a gate located 50-60 Å away in the central cavity. Structures of closed and open vertebrate CNG channels have been solved, but the conformational landscape of this allosteric gating remains to be elucidated and enriched. Here, we report structures of the cGMP-activated human cone photoreceptor CNGA3/CNGB3 channel in closed, intermediate, pre-open and open states in detergent or lipid nanodisc, all with fully bound cGMP. The pre-open and open states are obtained only in the lipid nanodisc, suggesting a critical role of lipids in tuning the energetic landscape of CNGA3/CNGB3 activation. The different states exhibit subunit-unique, incremental and distinct conformational rearrangements that originate in the CNBD, propagate through the gating ring to the transmembrane domain, and gradually open the S6 cavity gate. Our work illustrates a spatial conformational-change wave of allosteric gating of a vertebrate CNG channel by its natural ligand and provides an expanded framework for studying CNG properties and channelopathy.
    DOI:  https://doi.org/10.1038/s41467-023-39971-8
  22. Nat Commun. 2023 Jul 19. 14(1): 4342
    Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin.
    Alfredo Erazo-Oliveras, Mónica Muñoz-Vega, Mohamed Mlih, Venkataramana Thiriveedi, Michael L Salinas, Jaileen M Rivera-Rodríguez, Eunjoo Kim, Rachel C Wright, Xiaoli Wang, Kerstin K Landrock, Jennifer S Goldsby, Destiny A Mullens, Jatin Roper, Jason Karpac, Robert S Chapkin.
      Although the role of the Wnt pathway in colon carcinogenesis has been described previously, it has been recently demonstrated that Wnt signaling originates from highly dynamic nano-assemblies at the plasma membrane. However, little is known regarding the role of oncogenic APC in reshaping Wnt nanodomains. This is noteworthy, because oncogenic APC does not act autonomously and requires activation of Wnt effectors upstream of APC to drive aberrant Wnt signaling. Here, we demonstrate the role of oncogenic APC in increasing plasma membrane free cholesterol and rigidity, thereby modulating Wnt signaling hubs. This results in an overactivation of Wnt signaling in the colon. Finally, using the Drosophila sterol auxotroph model, we demonstrate the unique ability of exogenous free cholesterol to disrupt plasma membrane homeostasis and drive Wnt signaling in a wildtype APC background. Collectively, these findings provide a link between oncogenic APC, loss of plasma membrane homeostasis and CRC development.
    DOI:  https://doi.org/10.1038/s41467-023-39640-w
  23. Commun Biol. 2023 Jul 21. 6(1): 761
    Comprehensive analysis of intercellular communication in the thermogenic adipose niche.
    Farnaz Shamsi, Rongbin Zheng, Li-Lun Ho, Kaifu Chen, Yu-Hua Tseng.
      Brown adipose tissue (BAT) is responsible for regulating body temperature through adaptive thermogenesis. The ability of thermogenic adipocytes to dissipate chemical energy as heat counteracts weight gain and has gained considerable attention as a strategy against obesity. BAT undergoes major remodeling in a cold environment. This remodeling results from changes in the number and function of brown adipocytes, expanding the network of blood vessels and sympathetic nerves, and changes in the composition and function of immune cells. Such synergistic adaptation requires extensive crosstalk between individual cells in the tissue to coordinate their responses. To understand the mechanisms of intercellular communication in BAT, we apply the CellChat algorithm to single-cell transcriptomic data of mouse BAT. We construct an integrative network of the ligand-receptor interactome in BAT and identify the major signaling inputs and outputs of each cell type. By comparing the ligand-receptor interactions in BAT of mice housed at different environmental temperatures, we show that cold exposure enhances the intercellular interactions among the major cell types in BAT, including adipocytes, adipocyte progenitors, lymphatic and vascular endothelial cells, myelinated and non-myelinated Schwann cells, and immune cells. These interactions are predicted to regulate the remodeling of the extracellular matrix, the inflammatory response, angiogenesis, and neurite growth. Together, our integrative analysis of intercellular communications in BAT and their dynamic regulation in response to housing temperatures provides a new understanding of the mechanisms underlying BAT thermogenesis. The resources presented in this study offer a valuable platform for future investigations of BAT development and thermogenesis.
    DOI:  https://doi.org/10.1038/s42003-023-05140-2
  24. Proc Natl Acad Sci U S A. 2023 07 25. 120(30): e2210599120
    Small mitochondrial protein NERCLIN regulates cardiolipin homeostasis and mitochondrial ultrastructure.
    Svetlana Konovalova, Rubén Torregrosa-Muñumer, Pooja Manjunath, Xiaonan Liu, Sundar Baral, Kaneez Fatima, Minna Holopainen, Jouni Kvist, Jayasimman Rajendran, Yang Yang, Markku Varjosalo, Reijo Käkelä, Pentti Somerharju, Henna Tyynismaa.
      Cardiolipin (CL) is an essential phospholipid for mitochondrial structure and function. Here, we present a small mitochondrial protein, NERCLIN, as a negative regulator of CL homeostasis and mitochondrial ultrastructure. Primate-specific NERCLIN is expressed ubiquitously from the GRPEL2 locus on a tightly regulated low level. NERCLIN overexpression severely disrupts mitochondrial cristae structure and induces mitochondrial fragmentation. Proximity labeling and immunoprecipitation analysis suggested interactions of NERCLIN with CL synthesis and prohibitin complexes on the matrix side of the inner mitochondrial membrane. Lipid analysis indicated that NERCLIN regulates mitochondrial CL content. Furthermore, NERCLIN is responsive to heat stress ensuring OPA1 processing and cell survival. Thus, we propose that NERCLIN contributes to the stress-induced adaptation of mitochondrial dynamics. Our findings add NERCLIN to the group of recently identified small mitochondrial proteins with important regulatory functions.
    Keywords:  NERCLIN; OPA1; cardiolipin; prohibitins; small mitochondrial proteins
    DOI:  https://doi.org/10.1073/pnas.2210599120
  25. Nat Immunol. 2023 Jul 20.
    ThPOK is a critical multifaceted regulator of myeloid lineage development.
    Jayati Basu, Andre Olsson, Kyle Ferchen, Elizaveta K Titerina, Kashish Chetal, Emmanuelle Nicolas, Philip Czyzewicz, Dmitry Levchenko, Lu Ge, Xiang Hua, H Leighton Grimes, Nathan Salomonis, Dietmar J Kappes.
      The transcription factor ThPOK (encoded by Zbtb7b) is well known for its role as a master regulator of CD4 lineage commitment in the thymus. Here, we report an unexpected and critical role of ThPOK as a multifaceted regulator of myeloid lineage commitment, differentiation and maturation. Using reporter and knockout mouse models combined with single-cell RNA-sequencing, progenitor transfer and colony assays, we show that ThPOK controls monocyte-dendritic cell versus granulocyte lineage production during homeostatic differentiation, and serves as a brake for neutrophil maturation in granulocyte lineage-specified cells through transcriptional regulation of lineage-specific transcription factors and RNA via altered messenger RNA splicing to reprogram intron retention.
    DOI:  https://doi.org/10.1038/s41590-023-01549-3
  26. Nat Commun. 2023 07 19. 14(1): 4345
    Dual-color DNA-PAINT single-particle tracking enables extended studies of membrane protein interactions.
    Christian Niederauer, Chikim Nguyen, Miles Wang-Henderson, Johannes Stein, Sebastian Strauss, Alexander Cumberworth, Florian Stehr, Ralf Jungmann, Petra Schwille, Kristina A Ganzinger.
      DNA-PAINT based single-particle tracking (DNA-PAINT-SPT) has recently significantly enhanced observation times in in vitro SPT experiments by overcoming the constraints of fluorophore photobleaching. However, with the reported implementation, only a single target can be imaged and the technique cannot be applied straight to live cell imaging. Here we report on leveraging this technique from a proof-of-principle implementation to a useful tool for the SPT community by introducing simultaneous live cell dual-color DNA-PAINT-SPT for quantifying protein dimerization and tracking proteins in living cell membranes, demonstrating its improved performance over single-dye SPT.
    DOI:  https://doi.org/10.1038/s41467-023-40065-8
  27. Nat Neurosci. 2023 Jul 17.
    Identification of ligand-receptor pairs that drive human astrocyte development.
    Anna J Voss, Samantha N Lanjewar, Maureen M Sampson, Alexia King, Emily J Hill, Anson Sing, Caitlin Sojka, Tarun N Bhatia, Jennifer M Spangle, Steven A Sloan.
      Extrinsic signaling between diverse cell types is crucial for nervous system development. Ligand binding is a key driver of developmental processes. Nevertheless, it remains a significant challenge to disentangle which and how extrinsic signals act cooperatively to affect changes in recipient cells. In the developing human brain, cortical progenitors transition from neurogenesis to gliogenesis in a stereotyped sequence that is in part influenced by extrinsic ligands. Here we used published transcriptomic data to identify and functionally test five ligand-receptor pairs that synergistically drive human astrogenesis. We validate the synergistic contributions of TGFβ2, NLGN1, TSLP, DKK1 and BMP4 ligands on astrocyte development in both hCOs and primary fetal tissue. We confirm that the cooperative capabilities of these five ligands are greater than their individual capacities. Additionally, we discovered that their combinatorial effects converge in part on the mTORC1 signaling pathway, resulting in transcriptomic and morphological features of astrocyte development. Our data-driven framework can leverage single-cell and bulk genomic data to generate and test functional hypotheses surrounding cell-cell communication regulating neurodevelopmental processes.
    DOI:  https://doi.org/10.1038/s41593-023-01375-8
  28. Nat Immunol. 2023 Jul 20.
    Formation of bronchus-associated lymphoid tissue (BALT) for early life immune protection.
      
    DOI:  https://doi.org/10.1038/s41590-023-01573-3
  29. Nat Cell Biol. 2023 Jul 19.
    Advances and prospects for the Human BioMolecular Atlas Program (HuBMAP).
    HuBMAP Consortium
      The Human BioMolecular Atlas Program (HuBMAP) aims to create a multi-scale spatial atlas of the healthy human body at single-cell resolution by applying advanced technologies and disseminating resources to the community. As the HuBMAP moves past its first phase, creating ontologies, protocols and pipelines, this Perspective introduces the production phase: the generation of reference spatial maps of functional tissue units across many organs from diverse populations and the creation of mapping tools and infrastructure to advance biomedical research.
    DOI:  https://doi.org/10.1038/s41556-023-01194-w
  30. Nat Commun. 2023 07 17. 14(1): 4103
    Epigenetic mechanisms to propagate histone acetylation by p300/CBP.
    Masaki Kikuchi, Satoshi Morita, Masatoshi Wakamori, Shin Sato, Tomomi Uchikubo-Kamo, Takehiro Suzuki, Naoshi Dohmae, Mikako Shirouzu, Takashi Umehara.
      Histone acetylation is important for the activation of gene transcription but little is known about its direct read/write mechanisms. Here, we report cryogenic electron microscopy structures in which a p300/CREB-binding protein (CBP) multidomain monomer recognizes histone H4 N-terminal tail (NT) acetylation (ac) in a nucleosome and acetylates non-H4 histone NTs within the same nucleosome. p300/CBP not only recognized H4NTac via the bromodomain pocket responsible for reading, but also interacted with the DNA minor grooves via the outside of that pocket. This directed the catalytic center of p300/CBP to one of the non-H4 histone NTs. The primary target that p300 writes by reading H4NTac was H2BNT, and H2BNTac promoted H2A-H2B dissociation from the nucleosome. We propose a model in which p300/CBP replicates histone N-terminal tail acetylation within the H3-H4 tetramer to inherit epigenetic storage, and transcribes it from the H3-H4 tetramer to the H2B-H2A dimers to activate context-dependent gene transcription through local nucleosome destabilization.
    DOI:  https://doi.org/10.1038/s41467-023-39735-4
  31. Immunity. 2023 Jul 14. pii: S1074-7613(23)00278-9. [Epub ahead of print]
    Obesity-induced dysregulation of skin-resident PPARγ+ Treg cells promotes IL-17A-mediated psoriatic inflammation.
    Pulavendran Sivasami, Cody Elkins, Pamela P Diaz-Saldana, Kyndal Goss, Amy Peng, Michael Hamersky, Jennifer Bae, Miaoer Xu, Brian P Pollack, Edwin M Horwitz, Christopher D Scharer, Lindsey Seldin, Chaoran Li.
      Obesity is a major risk factor for psoriasis, but how obesity disrupts the regulatory mechanisms that keep skin inflammation in check is unclear. Here, we found that skin was enriched with a unique population of CD4+Foxp3+ regulatory T (Treg) cells expressing the nuclear receptor peroxisome proliferation-activated receptor gamma (PPARγ). PPARγ drove a distinctive transcriptional program and functional suppression of IL-17A+ γδ T cell-mediated psoriatic inflammation. Diet-induced obesity, however, resulted in a reduction of PPARγ+ skin Treg cells and a corresponding loss of control over IL-17A+ γδ T cell-mediated inflammation. Mechanistically, PPARγ+ skin Treg cells preferentially took up elevated levels of long-chain free fatty acids in obese mice, which led to cellular lipotoxicity, oxidative stress, and mitochondrial dysfunction. Harnessing the anti-inflammatory properties of these PPARγ+ skin Treg cells could have therapeutic potential for obesity-associated inflammatory skin diseases.
    Keywords:  IL-17A; PPARγ; Treg; free fatty acid; high-fat diet; immunometabolism; obesity; psoriasis; skin; γδ T cell
    DOI:  https://doi.org/10.1016/j.immuni.2023.06.021
  32. Proc Natl Acad Sci U S A. 2023 07 25. 120(30): e2217128120
    Slingshot homolog-1-mediated Nrf2 sequestration tips the balance from neuroprotection to neurodegeneration in Alzheimer's disease.
    Sara Cazzaro, Jung-A A Woo, Xinming Wang, Tian Liu, Shanon Rego, Teresa R Kee, Yeojung Koh, Edwin Vázquez-Rosa, Andrew A Pieper, David E Kang.
      Oxidative damage in the brain is one of the earliest drivers of pathology in Alzheimer's disease (AD) and related dementias, both preceding and exacerbating clinical symptoms. In response to oxidative stress, nuclear factor erythroid 2-related factor 2 (Nrf2) is normally activated to protect the brain from oxidative damage. However, Nrf2-mediated defense against oxidative stress declines in AD, rendering the brain increasingly vulnerable to oxidative damage. Although this phenomenon has long been recognized, its mechanistic basis has been a mystery. Here, we demonstrate through in vitro and in vivo models, as well as human AD brain tissue, that Slingshot homolog-1 (SSH1) drives this effect by acting as a counterweight to neuroprotective Nrf2 in response to oxidative stress and disease. Specifically, oxidative stress-activated SSH1 suppresses nuclear Nrf2 signaling by sequestering Nrf2 complexes on actin filaments and augmenting Kelch-like ECH-associated protein 1 (Keap1)-Nrf2 interaction, independently of SSH1 phosphatase activity. We also show that Ssh1 elimination in AD models increases Nrf2 activation, which mitigates tau and amyloid-β accumulation and protects against oxidative injury, neuroinflammation, and neurodegeneration. Furthermore, loss of Ssh1 preserves normal synaptic function and transcriptomic patterns in tauP301S mice. Importantly, we also show that human AD brains exhibit highly elevated interactions of Nrf2 with both SSH1 and Keap1. Thus, we demonstrate here a unique mode of Nrf2 blockade that occurs through SSH1, which drives oxidative damage and ensuing pathogenesis in AD. Strategies to inhibit SSH1-mediated Nrf2 suppression while preserving normal SSH1 catalytic function may provide new neuroprotective therapies for AD and related dementias.
    Keywords:  Nrf2; alzheimer; oxidative stress; slingshot; tauopathy
    DOI:  https://doi.org/10.1073/pnas.2217128120
  33. Nat Rev Immunol. 2023 Jul 17.
    Thousands of cGAS-like receptors described in animals.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-023-00917-2
  34. J Clin Invest. 2023 07 17. pii: e171965. [Epub ahead of print]133(14):
    Preserving mitochondria to treat hypertrophic cardiomyopathy: From rare mitochondrial DNA mutation to heart failure therapy?
    Abhinav Diwan.
      Hypertrophic cardiomyopathy and pathological cardiac hypertrophy are characterized by mitochondrial structural and functional abnormalities. In this issue of the JCI, Zhuang et al. discovered 1-deoxynojirimycin (DNJ) through a screen of mitochondrially targeted compounds. The authors described the effects of DNJ in restoring mitochondria and preventing cardiac myocyte hypertrophy in cellular models carrying a mutant mitochondrial gene, MT-RNR2, which is causally implicated in familial hypertrophic cardiomyopathy. DNJ worked via stabilization of the mitochondrial inner-membrane GTPase OPA1 and other, hitherto unknown, mechanisms to preserve mitochondrial crista and respiratory chain components. The discovery is likely to spur development of a class of therapeutics that restore mitochondrial health to prevent cardiomyopathy and heart failure.
    DOI:  https://doi.org/10.1172/JCI171965
  35. Nature. 2023 Jul 19.
    A cell-type-specific error-correction signal in the posterior parietal cortex.
    Jonathan Green, Carissa A Bruno, Lisa Traunmüller, Jennifer Ding, Siniša Hrvatin, Daniel E Wilson, Thomas Khodadad, Jonathan Samuels, Michael E Greenberg, Christopher D Harvey.
      Neurons in the posterior parietal cortex contribute to the execution of goal-directed navigation1 and other decision-making tasks2-4. Although molecular studies have catalogued more than 50 cortical cell types5, it remains unclear what distinct functions they have in this area. Here we identified a molecularly defined subset of somatostatin (Sst) inhibitory neurons that, in the mouse posterior parietal cortex, carry a cell-type-specific error-correction signal for navigation. We obtained repeatable experimental access to these cells using an adeno-associated virus in which gene expression is driven by an enhancer that functions specifically in a subset of Sst cells6. We found that during goal-directed navigation in a virtual environment, this subset of Sst neurons activates in a synchronous pattern that is distinct from the activity of surrounding neurons, including other Sst neurons. Using in vivo two-photon photostimulation and ex vivo paired patch-clamp recordings, we show that nearby cells of this Sst subtype excite each other through gap junctions, revealing a self-excitation circuit motif that contributes to the synchronous activity of this cell type. These cells selectively activate as mice execute course corrections for deviations in their virtual heading during navigation towards a reward location, for both self-induced and experimentally induced deviations. We propose that this subtype of Sst neurons provides a self-reinforcing and cell-type-specific error-correction signal in the posterior parietal cortex that may help with the execution and learning of accurate goal-directed navigation trajectories.
    DOI:  https://doi.org/10.1038/s41586-023-06357-1
  36. Nat Commun. 2023 07 17. 14(1): 4250
    Restoration of PITPNA in Type 2 diabetic human islets reverses pancreatic beta-cell dysfunction.
    Yu-Te Yeh, Chandan Sona, Xin Yan, Yunxiao Li, Adrija Pathak, Mark I McDermott, Zhigang Xie, Liangwen Liu, Anoop Arunagiri, Yuting Wang, Amaury Cazenave-Gassiot, Adhideb Ghosh, Ferdinand von Meyenn, Sivarajan Kumarasamy, Sonia M Najjar, Shiqi Jia, Markus R Wenk, Alexis Traynor-Kaplan, Peter Arvan, Sebastian Barg, Vytas A Bankaitis, Matthew N Poy.
      Defects in insulin processing and granule maturation are linked to pancreatic beta-cell failure during type 2 diabetes (T2D). Phosphatidylinositol transfer protein alpha (PITPNA) stimulates activity of phosphatidylinositol (PtdIns) 4-OH kinase to produce sufficient PtdIns-4-phosphate (PtdIns-4-P) in the trans-Golgi network to promote insulin granule maturation. PITPNA in beta-cells of T2D human subjects is markedly reduced suggesting its depletion accompanies beta-cell dysfunction. Conditional deletion of Pitpna in the beta-cells of Ins-Cre, Pitpnaflox/flox mice leads to hyperglycemia resulting from decreasing glucose-stimulated insulin secretion (GSIS) and reducing pancreatic beta-cell mass. Furthermore, PITPNA silencing in human islets confirms its role in PtdIns-4-P synthesis and leads to impaired insulin granule maturation and docking, GSIS, and proinsulin processing with evidence of ER stress. Restoration of PITPNA in islets of T2D human subjects reverses these beta-cell defects and identify PITPNA as a critical target linked to beta-cell failure in T2D.
    DOI:  https://doi.org/10.1038/s41467-023-39978-1
  37. Proc Natl Acad Sci U S A. 2023 Aug;120(31): e2302809120
    Prostaglandin E2 activates melanin-concentrating hormone neurons to drive diet-induced obesity.
    Lisa Z Fang, Victoria Linehan, Maria Licursi, Christian O Alberto, Jacob L Power, Matthew P Parsons, Michiru Hirasawa.
      Hypothalamic inflammation reduces appetite and body weight during inflammatory diseases, while promoting weight gain when induced by high-fat diet (HFD). How hypothalamic inflammation can induce opposite energy balance outcomes remains unclear. We found that prostaglandin E2 (PGE2), a key hypothalamic inflammatory mediator of sickness, also mediates diet-induced obesity (DIO) by activating appetite-promoting melanin-concentrating hormone (MCH) neurons in the hypothalamus in rats and mice. The effect of PGE2 on MCH neurons is excitatory at low concentrations while inhibitory at high concentrations, indicating that these neurons can bidirectionally respond to varying levels of inflammation. During prolonged HFD, endogenous PGE2 depolarizes MCH neurons through an EP2 receptor-mediated inhibition of the electrogenic Na+/K+-ATPase. Disrupting this mechanism by genetic deletion of EP2 receptors on MCH neurons is protective against DIO and liver steatosis in male and female mice. Thus, an inflammatory mediator can directly stimulate appetite-promoting neurons to exacerbate DIO and fatty liver.
    Keywords:  EP2 receptor; Na+/K+-ATPase; high-fat diet; hypothalamus; prostaglandin E2
    DOI:  https://doi.org/10.1073/pnas.2302809120
  38. Proc Natl Acad Sci U S A. 2023 07 25. 120(30): e2306572120
    T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity.
    Sharon A Sagan, Zahra Moinfar, Carson E Moseley, Ravi Dandekar, Collin M Spencer, Alan S Verkman, Ole Petter Ottersen, Raymond A Sobel, John Sidney, Alessandro Sette, Mark S Anderson, Lawrence Steinman, Michael R Wilson, Joseph J Sabatino, Scott S Zamvil.
      Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4-/-), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to AQP4. Here, we found that pathogenic AQP4 T cell epitopes bind MHC II with exceptionally high affinity. Examination of T cell receptor (TCR) α/β usage revealed that AQP4-specific T cells from AQP4-/- mice employed a distinct TCR repertoire and exhibited clonal expansion. Selective thymic AQP4 deficiency did not fully restore AQP4-reactive T cells, demonstrating that thymic negative selection alone did not account for AQP4-specific tolerance in WT mice. Indeed, AQP4-specific Th17 cells caused paralysis in recipient WT or B cell-deficient mice, which was followed by complete recovery that was associated with apoptosis of donor T cells. However, donor AQP4-reactive T cells survived and caused persistent paralysis in recipient mice deficient in both T and B cells or mice lacking T cells only. Thus, AQP4 CNS autoimmunity was limited by T cell-dependent deletion of AQP4-reactive T cells. In contrast, myelin oligodendrocyte glycoprotein (MOG)-specific T cells survived and caused sustained disease in WT mice. These findings underscore the importance of peripheral T cell deletional tolerance to AQP4, which may be relevant to understanding the balance of AQP4-reactive T cells in health and in NMO. T cell tolerance to AQP4, expressed in multiple tissues, is distinct from tolerance to MOG, an autoantigen restricted in its expression.
    Keywords:  Sjögren’s syndrome; T cell tolerance; aquaporin-4; molecular mimicry; neuromyelitis optica
    DOI:  https://doi.org/10.1073/pnas.2306572120
  39. Nature. 2023 Jul 21.
    Dementia risk linked to blood-protein imbalance in middle age.
    Lilly Tozer.
      
    Keywords:  Alzheimer's disease; Brain; Medical research; Proteomics
    DOI:  https://doi.org/10.1038/d41586-023-02374-2
  40. Cell. 2023 Jul 14. pii: S0092-8674(23)00691-8. [Epub ahead of print]
    Orphan quality control shapes network dynamics and gene expression.
    Kevin G Mark, SriDurgaDevi Kolla, Jacob D Aguirre, Danielle M Garshott, Stefan Schmitt, Diane L Haakonsen, Christina Xu, Lukas Kater, Georg Kempf, Brenda Martínez-González, David Akopian, Stephanie K See, Nicolas H Thomä, Michael Rapé.
      All eukaryotes require intricate protein networks to translate developmental signals into accurate cell fate decisions. Mutations that disturb interactions between network components often result in disease, but how the composition and dynamics of complex networks are established remains poorly understood. Here, we identify the E3 ligase UBR5 as a signaling hub that helps degrade unpaired subunits of multiple transcriptional regulators that act within a network centered on the c-Myc oncoprotein. Biochemical and structural analyses show that UBR5 binds motifs that only become available upon complex dissociation. By rapidly turning over unpaired transcription factor subunits, UBR5 establishes dynamic interactions between transcriptional regulators that allow cells to effectively execute gene expression while remaining receptive to environmental signals. We conclude that orphan quality control plays an essential role in establishing dynamic protein networks, which may explain the conserved need for protein degradation during transcription and offers opportunities to modulate gene expression in disease.
    Keywords:  MCRS1; MYC; UBR5; branched ubiquitin chain; orphan quality control; proteasome; stem cell; transcription factor; ubiquitin
    DOI:  https://doi.org/10.1016/j.cell.2023.06.015
  41. Science. 2023 Jul 21. 381(6655): 270-271
    Heart failure causes sleepless nights.
    Harvey Davis, David Attwell.
      Cardiac dysfunction triggers immune-mediated loss of pineal gland melatonin release.
    DOI:  https://doi.org/10.1126/science.adj0217
  42. Nat Commun. 2023 07 18. 14(1): 4302
    CellSighter: a neural network to classify cells in highly multiplexed images.
    Yael Amitay, Yuval Bussi, Ben Feinstein, Shai Bagon, Idan Milo, Leeat Keren.
      Multiplexed imaging enables measurement of multiple proteins in situ, offering an unprecedented opportunity to chart various cell types and states in tissues. However, cell classification, the task of identifying the type of individual cells, remains challenging, labor-intensive, and limiting to throughput. Here, we present CellSighter, a deep-learning based pipeline to accelerate cell classification in multiplexed images. Given a small training set of expert-labeled images, CellSighter outputs the label probabilities for all cells in new images. CellSighter achieves over 80% accuracy for major cell types across imaging platforms, which approaches inter-observer concordance. Ablation studies and simulations show that CellSighter is able to generalize its training data and learn features of protein expression levels, as well as spatial features such as subcellular expression patterns. CellSighter's design reduces overfitting, and it can be trained with only thousands or even hundreds of labeled examples. CellSighter also outputs a prediction confidence, allowing downstream experts control over the results. Altogether, CellSighter drastically reduces hands-on time for cell classification in multiplexed images, while improving accuracy and consistency across datasets.
    DOI:  https://doi.org/10.1038/s41467-023-40066-7
  43. Nat Commun. 2023 Jul 20. 14(1): 4385
    IL-1β turnover by the UBE2L3 ubiquitin conjugating enzyme and HECT E3 ligases limits inflammation.
    Vishwas Mishra, Anna Crespo-Puig, Callum McCarthy, Tereza Masonou, Izabela Glegola-Madejska, Alice Dejoux, Gabriella Dow, Matthew J G Eldridge, Luciano H Marinelli, Meihan Meng, Shijie Wang, Daniel J Bennison, Rebecca Morrison, Avinash R Shenoy.
      The cytokine interleukin-1β (IL-1β) has pivotal roles in antimicrobial immunity, but also incites inflammatory disease. Bioactive IL-1β is released following proteolytic maturation of the pro-IL-1β precursor by caspase-1. UBE2L3, a ubiquitin conjugating enzyme, promotes pro-IL-1β ubiquitylation and proteasomal disposal. However, actions of UBE2L3 in vivo and its ubiquitin ligase partners in this process are unknown. Here we report that deletion of Ube2l3 in mice reduces pro-IL-1β turnover in macrophages, leading to excessive mature IL-1β production, neutrophilic inflammation and disease following inflammasome activation. An unbiased RNAi screen identified TRIP12 and AREL1 E3 ligases of the Homologous to E6 C-terminus (HECT) family in adding destabilising K27-, K29- and K33- poly-ubiquitin chains on pro-IL-1β. We show that precursor abundance determines mature IL-1β production, and UBE2L3, TRIP12 and AREL1 limit inflammation by shrinking the cellular pool of pro-IL-1β. Our study uncovers fundamental processes governing IL-1β homeostasis and provides molecular insights that could be exploited to mitigate its adverse actions in disease.
    DOI:  https://doi.org/10.1038/s41467-023-40054-x
  44. Nat Aging. 2023 Jul 20.
    LONRF2 is a protein quality control ubiquitin ligase whose deficiency causes late-onset neurological deficits.
    Dan Li, Yoshikazu Johmura, Satoru Morimoto, Miyuki Doi, Keiko Nakanishi, Manabu Ozawa, Yuji Tsunekawa, Akane Inoue-Yamauchi, Hiroya Naruse, Takashi Matsukawa, Yukio Takeshita, Naoki Suzuki, Masashi Aoki, Ayumi Nishiyama, Xin Zeng, Chieko Konishi, Narumi Suzuki, Atsuya Nishiyama, Alexander Stephen Harris, Mariko Morita, Kiyoshi Yamaguchi, Yoichi Furukawa, Kenta Nakai, Shoji Tsuji, Satoshi Yamazaki, Yuji Yamanashi, Shoichi Shimada, Takashi Okada, Hideyuki Okano, Tatsushi Toda, Makoto Nakanishi.
      Protein misfolding is a major factor of neurodegenerative diseases. Post-mitotic neurons are highly susceptible to protein aggregates that are not diluted by mitosis. Therefore, post-mitotic cells may have a specific protein quality control system. Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons. LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins. Lonrf2-/- mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia. Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture. The shortening of neurites in MNs from patients with amyotrophic lateral sclerosis is rescued by ectopic expression of LONRF2. Our findings reveal that LONRF2 is a protein quality control ligase whose loss may contribute to MN degeneration and motor deficits.
    DOI:  https://doi.org/10.1038/s43587-023-00464-4
  45. Nat Commun. 2023 Jul 15. 14(1): 4225
    Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons.
    Yanan Liu, Longmiao Hu, Zhengzhen Wu, Kun Yuan, Guangliang Hong, Zhengke Lian, Juanjuan Feng, Na Li, Dali Li, Jiemin Wong, Jiekai Chen, Mingyao Liu, Jiangping He, Xiufeng Pang.
      Immunotherapy has become established as major treatment modality for multiple types of solid tumors, including colorectal cancer. Identifying novel immunotherapeutic targets to enhance anti-tumor immunity and sensitize current immune checkpoint blockade (ICB) in colorectal cancer is needed. Here we report the histone demethylase PHD finger protein 8 (PHF8, KDM7B), a Jumonji C domain-containing protein that erases repressive histone methyl marks, as an essential mediator of immune escape. Ablation the function of PHF8 abrogates tumor growth, activates anti-tumor immune memory, and augments sensitivity to ICB therapy in mouse models of colorectal cancer. Strikingly, tumor PHF8 deletion stimulates a viral mimicry response in colorectal cancer cells, where the depletion of key components of endogenous nucleic acid sensing diminishes PHF8 loss-meditated antiviral immune responses and anti-tumor effects in vivo. Mechanistically, PHF8 inhibition elicits H3K9me3-dependent retrotransposon activation by promoting proteasomal degradation of the H3K9 methyltransferase SETDB1 in a demethylase-independent manner. Moreover, PHF8 expression is anti-correlated with canonical immune signatures and antiviral immune responses in human colorectal adenocarcinoma. Overall, our study establishes PHF8 as an epigenetic checkpoint, and targeting PHF8 is a promising viral mimicry-inducing approach to enhance intrinsic anti-tumor immunity or to conquer immune resistance.
    DOI:  https://doi.org/10.1038/s41467-023-39943-y
  46. Aging Cell. 2023 Jul 18. e13915
    Transcriptomes of human primary skin fibroblasts of healthy individuals reveal age-associated mRNAs and long noncoding RNAs.
    Dimitrios Tsitsipatis, Jennifer L Martindale, Krystyna Mazan-Mamczarz, Allison B Herman, Yulan Piao, Nirad Banskota, Jen-Hao Yang, Linna Cui, Carlos Anerillas, Ming-Wen Chang, Mary Kaileh, Rachel Munk, Xiaoling Yang, Ceereena Ubaida-Mohien, Chee W Chia, Ajoy C Karikkineth, Linda Zukley, Jarod D'Agostino, Kotb Abdelmohsen, Nathan Basisty, Supriyo De, Luigi Ferrucci, Myriam Gorospe.
      Changes in the transcriptomes of human tissues with advancing age are poorly cataloged. Here, we sought to identify the coding and long noncoding RNAs present in cultured primary skin fibroblasts collected from 82 healthy individuals across a wide age spectrum (22-89 years old) who participated in the GESTALT (Genetic and Epigenetic Signatures of Translational Aging Laboratory Testing) study of the National Institute on Aging, NIH. Using high-throughput RNA sequencing and a linear regression model, we identified 1437 coding RNAs (mRNAs) and 1177 linear and circular long noncoding (lncRNAs) that were differentially abundant as a function of age. Gene set enrichment analysis (GSEA) revealed select transcription factors implicated in coordinating the transcription of subsets of differentially abundant mRNAs, while long noncoding RNA enrichment analysis (LncSEA) identified RNA-binding proteins predicted to participate in the age-associated lncRNA profiles. In summary, we report age-associated changes in the global transcriptome, coding and noncoding, from healthy human skin fibroblasts and propose that these transcripts may serve as biomarkers and therapeutic targets in aging skin.
    Keywords:  aging; circular RNAs; human dermal fibroblasts; long noncoding RNAs; messenger RNAs; transcriptome
    DOI:  https://doi.org/10.1111/acel.13915
  47. Nat Commun. 2023 07 18. 14(1): 4316
    Nutritional redundancy in the human diet and its application in phenotype association studies.
    Xu-Wen Wang, Yang Hu, Giulia Menichetti, Francine Grodstein, Shilpa N Bhupathiraju, Qi Sun, Xuehong Zhang, Frank B Hu, Scott T Weiss, Yang-Yu Liu.
      Studying human dietary intake may help us identify effective measures to treat or prevent many chronic diseases whose natural histories are influenced by nutritional factors. Here, by examining five cohorts with dietary intake data collected on different time scales, we show that the food intake profile varies substantially across individuals and over time, while the nutritional intake profile appears fairly stable. We refer to this phenomenon as 'nutritional redundancy' and attribute it to the nested structure of the food-nutrient network. This network enables us to quantify the level of nutritional redundancy for each diet assessment of any individual. Interestingly, this nutritional redundancy measure does not strongly correlate with any classical healthy diet scores, but its performance in predicting healthy aging shows comparable strength. Moreover, after adjusting for age, we find that a high nutritional redundancy is associated with lower risks of cardiovascular disease and type 2 diabetes.
    DOI:  https://doi.org/10.1038/s41467-023-39836-0
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