bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022–12–04
fifty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Expanding registered reports.
  2. Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development.
  3. G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis.
  4. mTORC1 links pathology in experimental models of Still's disease and macrophage activation syndrome.
  5. Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.
  6. A conversation on bringing the Registered Report format to Nature Communications.
  7. Greater genetic diversity is needed in human pluripotent stem cell models.
  8. Epigenetic regulation of white adipose tissue plasticity and energy metabolism by nucleosome binding HMGN proteins.
  9. Natural mouse microbes transiently block innate responses to allergens.
  10. A p38α-BLIMP1 signalling pathway is essential for plasma cell differentiation.
  11. Molecular basis for DNA recognition by the maternal pioneer transcription factor FoxH1.
  12. The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis.
  13. Genetically personalised organ-specific metabolic models in health and disease.
  14. Low-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes.
  15. Deciphering the heterogeneity of the Lyve1+ perivascular macrophages in the mouse brain.
  16. Early T-bet promotes LFA1 upregulation required for CD8+ effector and memory T cell development.
  17. A unified computational framework for single-cell data integration with optimal transport.
  18. Mitochondrial RNA stimulates beige adipocyte development in young mice.
  19. These monkeypox researchers warned that the disease would go global.
  20. Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis.
  21. Role of CXCR5+ CD8+ T cells in human immunodeficiency virus-1 infection.
  22. Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells.
  23. Protein-Peptide Turnover Profiling reveals the order of PTM addition and removal during protein maturation.
  24. Self-cleaving guide RNAs enable pharmacological selection of precise gene editing events in vivo.
  25. Secreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice.
  26. Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation.
  27. Follicular CD8+ T Cells Are Elevated in HIV Infection and Induce PD-L1 on B Cells.
  28. Toll-like receptors control the accumulation of neutrophils in lymph nodes that expand CD4+ T cells during experimental autoimmune encephalomyelitis.
  29. Structures of the eukaryotic ribosome and its translational states in situ.
  30. Fishing with autoantibodies nets a gut bacteria that drives arthritis.
  31. Membrane-mediated protein interactions drive membrane protein organization.
  32. Structures of the holo CRISPR RNA-guided transposon integration complex.
  33. Gene activation guided by nascent RNA-bound transcription factors.
  34. Discrete LAT condensates encode antigen information from single pMHC:TCR binding events.
  35. CryoEM structure and assembly mechanism of a bacterial virus genome gatekeeper.
  36. A self-powered ingestible wireless biosensing system for real-time in situ monitoring of gastrointestinal tract metabolites.
  37. IL6 supports long-term expansion of hepatocytes in vitro.
  38. Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.
  39. PCGF1-PRC1 links chromatin repression with DNA replication during hematopoietic cell lineage commitment.
  40. GSK3α phosphorylates dynamin-2 to promote GLUT4 endocytosis in muscle cells.
  41. Fungal sensing by dectin-1 directs the non-pathogenic polarization of TH17 cells through balanced type I IFN responses in human DCs.
  42. Mitochondrial copper in human genetic disorders.
  43. Structural basis for lipid and copper regulation of the ABC transporter MsbA.
  44. Early microbial exposure shapes adult immunity by altering CD8+ T cell development.
  45. Immunosuppressive biomaterial-based therapeutic vaccine to treat multiple sclerosis via re-establishing immune tolerance.
  46. Mitochondrial fragmentation and ROS signaling in wound response and repair.
  47. Loss of function of CMPK2 causes mitochondria deficiency and brain calcification.
  48. Single-cell multiomics reveals the complexity of TGFβ signalling to chromatin in iPSC-derived kidney organoids.
  49. Anti-fungal role for type I IFN as dectin-1 triggers non-pathogenic TH17 cell development.
  50. SOTIP is a versatile method for microenvironment modeling with spatial omics data.
  1. Nat Commun. 2022 Nov 28. 13(1): 7267
    Expanding registered reports.
      
    DOI:  https://doi.org/10.1038/s41467-022-34107-w
  2. Nat Commun. 2022 Dec 01. 13(1): 7397
    Golgipathies reveal the critical role of the sorting machinery in brain and skeletal development.
    Vincent El Ghouzzi, Gaelle Boncompain.
      
    DOI:  https://doi.org/10.1038/s41467-022-35101-y
  3. Nat Commun. 2022 Dec 01. 13(1): 7408
    G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis.
    Ewa Bielczyk-Maczynska, Meng Zhao, Peter-James H Zushin, Theresia M Schnurr, Hyun-Jung Kim, Jiehan Li, Pratima Nallagatla, Panjamaporn Sangwung, Chong Y Park, Cameron Cornn, Andreas Stahl, Katrin J Svensson, Joshua W Knowles.
      Human genetics has been instrumental in identification of genetic variants linked to type 2 diabetes. Recently a rare, putative loss-of-function mutation in the orphan G-protein coupled receptor 151 (GPR151) was found to be associated with lower odds ratio for type 2 diabetes, but the mechanism behind this association has remained elusive. Here we show that Gpr151 is a fasting- and glucagon-responsive hepatic gene which regulates hepatic gluconeogenesis. Gpr151 ablation in mice leads to suppression of hepatic gluconeogenesis genes and reduced hepatic glucose production in response to pyruvate. Importantly, the restoration of hepatic Gpr151 levels in the Gpr151 knockout mice reverses the reduced hepatic glucose production. In this work, we establish a previously unknown role of Gpr151 in the liver that provides an explanation to the lowered type 2 diabetes risk in individuals with nonsynonymous mutations in GPR151.
    DOI:  https://doi.org/10.1038/s41467-022-35069-9
  4. Nat Commun. 2022 Nov 28. 13(1): 6915
    mTORC1 links pathology in experimental models of Still's disease and macrophage activation syndrome.
    Zhengping Huang, Xiaomeng You, Liang Chen, Yan Du, Kailey Brodeur, Hyuk Jee, Qiang Wang, Grace Linder, Roxane Darbousset, Pierre Cunin, Margaret H Chang, Alexandra Wactor, Brian M Wauford, Marc J C Todd, Kevin Wei, Ying Li, Anais Levescot, Yoichiro Iwakura, Virginia Pascual, Nicole E Baldwin, Pierre Quartier, Tianwang Li, Maria T Gianatasio, Robert P Hasserjian, Lauren A Henderson, David B Sykes, Elizabeth D Mellins, Scott W Canna, Julia F Charles, Peter A Nigrovic, Pui Y Lee.
      Still's disease is a severe inflammatory syndrome characterized by fever, skin rash and arthritis affecting children and adults. Patients with Still's disease may also develop macrophage activation syndrome, a potentially fatal complication of immune dysregulation resulting in cytokine storm. Here we show that mTORC1 (mechanistic target of rapamycin complex 1) underpins the pathology of Still's disease and macrophage activation syndrome. Single-cell RNA sequencing in a murine model of Still's disease shows preferential activation of mTORC1 in monocytes; both mTOR inhibition and monocyte depletion attenuate disease severity. Transcriptomic data from patients with Still's disease suggest decreased expression of the mTORC1 inhibitors TSC1/TSC2 and an mTORC1 gene signature that strongly correlates with disease activity and treatment response. Unrestricted activation of mTORC1 by Tsc2 deletion in mice is sufficient to trigger a Still's disease-like syndrome, including both inflammatory arthritis and macrophage activation syndrome with hemophagocytosis, a cellular manifestation that is reproduced in human monocytes by CRISPR/Cas-mediated deletion of TSC2. Consistent with this observation, hemophagocytic histiocytes from patients with macrophage activation syndrome display prominent mTORC1 activity. Our study suggests a mechanistic link of mTORC1 to inflammation that connects the pathogenesis of Still's disease and macrophage activation syndrome.
    DOI:  https://doi.org/10.1038/s41467-022-34480-6
  5. Nat Commun. 2022 Nov 28. 13(1): 7338
    Lysosomal damage drives mitochondrial proteome remodelling and reprograms macrophage immunometabolism.
    Claudio Bussi, Tiaan Heunis, Enrica Pellegrino, Elliott M Bernard, Nourdine Bah, Mariana Silva Dos Santos, Pierre Santucci, Beren Aylan, Angela Rodgers, Antony Fearns, Julia Mitschke, Christopher Moore, James I MacRae, Maria Greco, Thomas Reinheckel, Matthias Trost, Maximiliano G Gutierrez.
      Transient lysosomal damage after infection with cytosolic pathogens or silica crystals uptake results in protease leakage. Whether limited leakage of lysosomal contents into the cytosol affects the function of cytoplasmic organelles is unknown. Here, we show that sterile and non-sterile lysosomal damage triggers a cell death independent proteolytic remodelling of the mitochondrial proteome in macrophages. Mitochondrial metabolic reprogramming required leakage of lysosomal cathepsins and was independent of mitophagy, mitoproteases and proteasome degradation. In an in vivo mouse model of endomembrane damage, live lung macrophages that internalised crystals displayed impaired mitochondrial function. Single-cell RNA-sequencing revealed that lysosomal damage skewed metabolic and immune responses in alveolar macrophages subsets with increased lysosomal content. Functionally, drug modulation of macrophage metabolism impacted host responses to Mycobacterium tuberculosis infection in an endomembrane damage dependent way. This work uncovers an inter-organelle communication pathway, providing a general mechanism by which macrophages undergo mitochondrial metabolic reprograming after endomembrane damage.
    DOI:  https://doi.org/10.1038/s41467-022-34632-8
  6. Nat Commun. 2022 Nov 28. 13(1): 7268
    A conversation on bringing the Registered Report format to Nature Communications.
      
    DOI:  https://doi.org/10.1038/s41467-022-34325-2
  7. Nat Commun. 2022 Nov 26. 13(1): 7301
    Greater genetic diversity is needed in human pluripotent stem cell models.
    Sulagna Ghosh, Ralda Nehme, Lindy E Barrett.
      
    DOI:  https://doi.org/10.1038/s41467-022-34940-z
  8. Nat Commun. 2022 Nov 26. 13(1): 7303
    Epigenetic regulation of white adipose tissue plasticity and energy metabolism by nucleosome binding HMGN proteins.
    Ravikanth Nanduri, Takashi Furusawa, Alexei Lobanov, Bing He, Carol Xie, Kimia Dadkhah, Michael C Kelly, Oksana Gavrilova, Frank J Gonzalez, Michael Bustin.
      White adipose tissue browning is a key metabolic process controlled by epigenetic factors that facilitate changes in gene expression leading to altered cell identity. We find that male mice lacking the nucleosome binding proteins HMGN1 and HMGN2 (DKO mice), show decreased body weight and inguinal WAT mass, but elevated food intake, WAT browning and energy expenditure. DKO white preadipocytes show reduced chromatin accessibility and lower FRA2 and JUN binding at Pparγ and Pparα promoters. White preadipocytes and mouse embryonic fibroblasts from DKO mice show enhanced rate of differentiation into brown-like adipocytes. Differentiating DKO adipocytes show reduced H3K27ac levels at white adipocyte-specific enhancers but elevated H3K27ac levels at brown adipocyte-specific enhancers, suggesting a faster rate of change in cell identity, from white to brown-like adipocytes. Thus, HMGN proteins function as epigenetic factors that stabilize white adipocyte cell identity, thereby modulating the rate of white adipose tissue browning and affecting energy metabolism in mice.
    DOI:  https://doi.org/10.1038/s41467-022-34964-5
  9. Nat Immunol. 2022 Dec 02.
    Natural mouse microbes transiently block innate responses to allergens.
      
    DOI:  https://doi.org/10.1038/s41590-022-01352-6
  10. Nat Commun. 2022 Nov 28. 13(1): 7321
    A p38α-BLIMP1 signalling pathway is essential for plasma cell differentiation.
    Jianfeng Wu, Kang Yang, Shaowei Cai, Xiaohan Zhang, Lichen Hu, Fanjia Lin, Su-Qin Wu, Changchun Xiao, Wen-Hsien Liu, Jiahuai Han.
      Plasma cells (PC) are antibody-secreting cells and terminal effectors in humoral responses. PCs differentiate directly from activated B cells in response to T cell-independent (TI) antigens or from germinal center B (GCB) cells in T cell-dependent (TD) antigen-induced humoral responses, both of which pathways are essentially regulated by the transcription factor BLIMP1. The p38 mitogen-activated protein kinase isoforms have already been implicated in B cell development, but the precise role of p38α in B cell differentiation is still largely unknown. Here we show that PC differentiation and antibody responses are severely impaired in mice with B cell-specific deletion of p38α, while B cell development and the GCB cell response are spared. By utilizing a Blimp1 reporter mouse model, we show that p38α-deficiency results in decreased BLIMP1 expression. p38α-driven BLIMP1 up-regulation is required for both TI and TD PCs differentiation. By combining CRISPR/Cas9 screening and other approaches, we identify TCF3, TCF4 and IRF4 as downstream effectors of p38α to control PC differentiation via Blimp1 transcription. This study thus identifies an important signalling pathway underpinning PC differentiation upstream of BLIMP1, and points to a highly specialized and non-redundant role for p38α among p38 isoforms.
    DOI:  https://doi.org/10.1038/s41467-022-34969-0
  11. Nat Commun. 2022 Nov 26. 13(1): 7279
    Molecular basis for DNA recognition by the maternal pioneer transcription factor FoxH1.
    Radoslaw Pluta, Eric Aragón, Nicholas A Prescott, Lidia Ruiz, Rebeca A Mees, Blazej Baginski, Julia R Flood, Pau Martin-Malpartida, Joan Massagué, Yael David, Maria J Macias.
      Forkhead box H1 (FoxH1) is an essential maternal pioneer factor during embryonic development that binds to specific GG/GT-containing DNA target sequences. Here we have determined high-resolution structures of three FoxH1 proteins (from human, frog and fish species) and four DNAs to clarify the way in which FoxH1 binds to these sites. We found that the protein-DNA interactions extend to both the minor and major DNA grooves and are thus almost twice as extensive as those of other FOX family members. Moreover, we identified two specific amino acid changes in FoxH1 that allowed the recognition of GG/GT motifs. Consistent with the pioneer factor activity of FoxH1, we found that its affinity for nucleosomal DNA is even higher than for linear DNA fragments. The structures reported herein illustrate how FoxH1 binding to distinct DNA sites provides specificity and avoids cross-regulation by other FOX proteins that also operate during the maternal-zygotic transition and select canonical forkhead sites.
    DOI:  https://doi.org/10.1038/s41467-022-34925-y
  12. Nat Commun. 2022 Nov 30. 13(1): 7375
    The E3 ubiquitin ligase WWP2 regulates pro-fibrogenic monocyte infiltration and activity in heart fibrosis.
    Huimei Chen, Gabriel Chew, Nithya Devapragash, Jui Zhi Loh, Kevin Y Huang, Jing Guo, Shiyang Liu, Elisabeth Li Sa Tan, Shuang Chen, Nicole Gui Zhen Tee, Masum M Mia, Manvendra K Singh, Aihua Zhang, Jacques Behmoaras, Enrico Petretto.
      Non-ischemic cardiomyopathy (NICM) can cause left ventricular dysfunction through interstitial fibrosis, which corresponds to the failure of cardiac tissue remodeling. Recent evidence implicates monocytes/macrophages in the etiopathology of cardiac fibrosis, but giving their heterogeneity and the antagonizing roles of macrophage subtypes in fibrosis, targeting these cells has been challenging. Here we focus on WWP2, an E3 ubiquitin ligase that acts as a positive genetic regulator of human and murine cardiac fibrosis, and show that myeloid specific deletion of WWP2 reduces cardiac fibrosis in hypertension-induced NICM. By using single cell RNA sequencing analysis of immune cells in the same model, we establish the functional heterogeneity of macrophages and define an early pro-fibrogenic phase of NICM that is driven by Ccl5-expressing Ly6chigh monocytes. Among cardiac macrophage subtypes, WWP2 dysfunction primarily affects Ly6chigh monocytes via modulating Ccl5, and consequentially macrophage infiltration and activation, which contributes to reduced myofibroblast trans-differentiation. WWP2 interacts with transcription factor IRF7, promoting its non-degradative mono-ubiquitination, nuclear translocation and transcriptional activity, leading to upregulation of Ccl5 at transcriptional level. We identify a pro-fibrogenic macrophage subtype in non-ischemic cardiomyopathy, and demonstrate that WWP2 is a key regulator of IRF7-mediated Ccl5/Ly6chigh monocyte axis in heart fibrosis.
    DOI:  https://doi.org/10.1038/s41467-022-34971-6
  13. Nat Commun. 2022 Nov 29. 13(1): 7356
    Genetically personalised organ-specific metabolic models in health and disease.
    Carles Foguet, Yu Xu, Scott C Ritchie, Samuel A Lambert, Elodie Persyn, Artika P Nath, Emma E Davenport, David J Roberts, Dirk S Paul, Emanuele Di Angelantonio, John Danesh, Adam S Butterworth, Christopher Yau, Michael Inouye.
      Understanding how genetic variants influence disease risk and complex traits (variant-to-function) is one of the major challenges in human genetics. Here we present a model-driven framework to leverage human genome-scale metabolic networks to define how genetic variants affect biochemical reaction fluxes across major human tissues, including skeletal muscle, adipose, liver, brain and heart. As proof of concept, we build personalised organ-specific metabolic flux models for 524,615 individuals of the INTERVAL and UK Biobank cohorts and perform a fluxome-wide association study (FWAS) to identify 4312 associations between personalised flux values and the concentration of metabolites in blood. Furthermore, we apply FWAS to identify 92 metabolic fluxes associated with the risk of developing coronary artery disease, many of which are linked to processes previously described to play in role in the disease. Our work demonstrates that genetically personalised metabolic models can elucidate the downstream effects of genetic variants on biochemical reactions involved in common human diseases.
    DOI:  https://doi.org/10.1038/s41467-022-35017-7
  14. Nat Commun. 2022 Nov 28. 13(1): 7324
    Low-dose IL-2 reduces IL-21+ T cell frequency and induces anti-inflammatory gene expression in type 1 diabetes.
    Jia-Yuan Zhang, Fiona Hamey, Dominik Trzupek, Marius Mickunas, Mercede Lee, Leila Godfrey, Jennie H M Yang, Marcin L Pekalski, Jane Kennet, Frank Waldron-Lynch, Mark L Evans, Timothy I M Tree, Linda S Wicker, John A Todd, Ricardo C Ferreira.
      Despite early clinical successes, the mechanisms of action of low-dose interleukin-2 (LD-IL-2) immunotherapy remain only partly understood. Here we examine the effects of interval administration of low-dose recombinant IL-2 (iLD-IL-2) in type 1 diabetes using high-resolution single-cell multiomics and flow cytometry on longitudinally-collected peripheral blood samples. Our results confirm that iLD-IL-2 selectively expands thymic-derived FOXP3+HELIOS+ regulatory T cells and CD56bright NK cells, and show that the treatment reduces the frequency of IL-21-producing CD4+ T cells and of two innate-like mucosal-associated invariant T and Vγ9Vδ2 CD8+ T cell subsets. The cellular changes induced by iLD-IL-2 associate with an anti-inflammatory gene expression signature, which remains detectable in all T and NK cell subsets analysed one month after treatment. These findings warrant investigations into the potential longer-term clinical benefits of iLD-IL-2 in immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-022-34162-3
  15. Nat Commun. 2022 Nov 30. 13(1): 7366
    Deciphering the heterogeneity of the Lyve1+ perivascular macrophages in the mouse brain.
    C Siret, M van Lessen, J Bavais, H W Jeong, S K Reddy Samawar, K Kapupara, S Wang, M Simic, L de Fabritus, A Tchoghandjian, M Fallet, H Huang, S Sarrazin, M H Sieweke, R Stumm, L Sorokin, R H Adams, S Schulte-Merker, F Kiefer, S A van de Pavert.
      Perivascular macrophages (pvMs) are associated with cerebral vasculature and mediate brain drainage and immune regulation. Here, using reporter mouse models, whole brain and section immunofluorescence, flow cytometry, and single cell RNA sequencing, besides the Lyve1+F4/80+CD206+CX3CR1+ pvMs, we identify a CX3CR1- pvM population that shares phagocytic functions and location. Furthermore, the brain parenchyma vasculature mostly hosts Lyve1+MHCII- pvMs with low to intermediate CD45 expression. Using the double Cx3cr1GFP x Cx3cr1-Cre;RosatdT reporter mice for finer mapping of the lineages, we establish that CD45lowCX3CR1- pvMs are derived from CX3CR1+ precursors and require PU.1 during their ontogeny. In parallel, results from the Cxcr4-CreErt2;Rosa26tdT lineage tracing model support a bone marrow-independent replenishment of all Lyve1+ pvMs in the adult mouse brain. Lastly, flow cytometry and 3D immunofluorescence analysis uncover increased percentage of pvMs following photothrombotic induced stroke. Our results thus show that the parenchymal pvM population is more heterogenous than previously described, and includes a CD45low and CX3CR1- pvM population.
    DOI:  https://doi.org/10.1038/s41467-022-35166-9
  16. J Exp Med. 2023 Feb 06. pii: e20191287. [Epub ahead of print]220(2):
    Early T-bet promotes LFA1 upregulation required for CD8+ effector and memory T cell development.
    Gretchen Harms Pritchard, Anthony T Phan, David A Christian, Trevor J Blain, Qun Fang, John Johnson, Nathan H Roy, Lindsey Shallberg, Ross M Kedl, Christopher A Hunter.
      The T-box transcription factor T-bet is regarded as a "master regulator" of CD4+ Th1 differentiation and IFN-γ production. However, in multiple models of infection, T-bet appears less critical for CD8+ T cell expansion and effector function. Here, we show that following vaccination with a replication-deficient strain of Toxoplasma gondii, CD8+ T cell expression of T-bet is required for optimal expansion of parasite-specific effector CD8+ T cells. Analysis of the early events associated with T cell activation reveals that the α chain of LFA1, CD11a, is a target of T-bet, and T-bet is necessary for CD8+ T cell upregulation of this integrin, which influences the initial priming of CD8+ effector T cells. We propose that the early expression of T-bet represents a T cell-intrinsic factor that optimizes T-DC interactions necessary to generate effector responses.
    DOI:  https://doi.org/10.1084/jem.20191287
  17. Nat Commun. 2022 Dec 01. 13(1): 7419
    A unified computational framework for single-cell data integration with optimal transport.
    Kai Cao, Qiyu Gong, Yiguang Hong, Lin Wan.
      Single-cell data integration can provide a comprehensive molecular view of cells. However, how to integrate heterogeneous single-cell multi-omics as well as spatially resolved transcriptomic data remains a major challenge. Here we introduce uniPort, a unified single-cell data integration framework that combines a coupled variational autoencoder (coupled-VAE) and minibatch unbalanced optimal transport (Minibatch-UOT). It leverages both highly variable common and dataset-specific genes for integration to handle the heterogeneity across datasets, and it is scalable to large-scale datasets. uniPort jointly embeds heterogeneous single-cell multi-omics datasets into a shared latent space. It can further construct a reference atlas for gene imputation across datasets. Meanwhile, uniPort provides a flexible label transfer framework to deconvolute heterogeneous spatial transcriptomic data using an optimal transport plan, instead of embedding latent space. We demonstrate the capability of uniPort by applying it to integrate a variety of datasets, including single-cell transcriptomics, chromatin accessibility, and spatially resolved transcriptomic data.
    DOI:  https://doi.org/10.1038/s41467-022-35094-8
  18. Nat Metab. 2022 Nov 28.
    Mitochondrial RNA stimulates beige adipocyte development in young mice.
    Anh Cuong Hoang, László Sasi-Szabó, Tibor Pál, Tamás Szabó, Victoria Diedrich, Annika Herwig, Kathrin Landgraf, Antje Körner, Tamás Röszer.
      Childhood obesity is a serious public health crisis and a critical factor that determines future obesity prevalence. Signals affecting adipocyte development in early postnatal life have a strong potential to trigger childhood obesity; however, these signals are still poorly understood. We show here that mitochondrial (mt)RNA efflux stimulates transcription of nuclear-encoded genes for mitobiogenesis and thermogenesis in adipocytes of young mice and human infants. While cytosolic mtRNA is a potential trigger of the interferon (IFN) response, young adipocytes lack such a response to cytosolic mtRNA due to the suppression of IFN regulatory factor (IRF)7 expression by vitamin D receptor signalling. Adult and obese adipocytes, however, strongly express IRF7 and mount an IFN response to cytosolic mtRNA. In turn, suppressing IRF7 expression in adult adipocytes restores mtRNA-induced mitobiogenesis and thermogenesis and eventually mitigates obesity. Retrograde mitochondrion-to-nucleus signalling by mtRNA is thus a mechanism to evoke thermogenic potential during early adipocyte development and to protect against obesity.
    DOI:  https://doi.org/10.1038/s42255-022-00683-w
  19. Nature. 2022 12;612(7938): 22-23
    These monkeypox researchers warned that the disease would go global.
    Paul Adepoju.
      
    Keywords:  Epidemiology; Health care; Virology
    DOI:  https://doi.org/10.1038/d41586-022-04155-9
  20. Nat Commun. 2022 Dec 01. 13(1): 7404
    Dietary glucosamine overcomes the defects in αβ-T cell ontogeny caused by the loss of de novo hexosamine biosynthesis.
    Guy Werlen, Mei-Ling Li, Luca Tottone, Victoria da Silva-Diz, Xiaoyang Su, Daniel Herranz, Estela Jacinto.
      T cell development requires the coordinated rearrangement of T cell receptor (TCR) gene segments and the expression of either αβ or γδ TCR. However, whether and how de novo synthesis of nutrients contributes to thymocyte commitment to either lineage remains unclear. Here, we find that T cell-specific deficiency in glutamine:fructose-6-phosphate aminotransferase 1 (GFAT1), the rate-limiting enzyme of the de novo hexosamine biosynthesis pathway (dn-HBP), attenuates hexosamine levels, blunts N-glycosylation of TCRβ chains, reduces surface expression of key developmental receptors, thus impairing αβ-T cell ontogeny. GFAT1 deficiency triggers defects in N-glycans, increases the unfolded protein response, and elevates  γδ-T cell numbers despite reducing γδ-TCR diversity. Enhancing TCR expression or PI3K/Akt signaling does not reverse developmental defects. Instead, dietary supplementation with the salvage metabolite, glucosamine, and an α-ketoglutarate analogue partially restores αβ-T cell development in GFAT1T-/- mice, while fully rescuing it in ex vivo fetal thymic organ cultures. Thus, dn-HBP fulfils, while salvage nutrients partially satisfy, the elevated demand for hexosamines during early T cell development.
    DOI:  https://doi.org/10.1038/s41467-022-35014-w
  21. Front Microbiol. 2022 ;13 998058
    Role of CXCR5+ CD8+ T cells in human immunodeficiency virus-1 infection.
    Leiqiong Gao, Jing Zhou, Lilin Ye.
      Human immunodeficiency virus (HIV) infection can be effectively suppressed by life-long administration of combination antiretroviral therapy (cART). However, the viral rebound can occur upon cART cessation due to the long-term presence of HIV reservoirs, posing a considerable barrier to drug-free viral remission. Memory CD4+ T cell subsets, especially T follicular helper (T FH ) cells that reside in B-cell follicles within lymphoid tissues, are regarded as the predominant cellular compartment of the HIV reservoir. Substantial evidence indicates that HIV-specific CD8+ T cell-mediated cellular immunity can sustain long-term disease-free and transmission-free HIV control in elite controllers. However, most HIV cure strategies that rely on expanded HIV-specific CD8+ T cells for virus control are likely to fail due to cellular exhaustion and T FH reservoir-specialized anatomical structures that isolate HIV-specific CD8+ T cell entry into B-cell follicles. Loss of stem-like memory properties is a key feature of exhaustion. Recent studies have found that CXC chemokine receptor type 5 (CXCR5)-expressing HIV-specific CD8+ T cells are memory-like CD8+ T cells that can migrate into B-cell follicles to execute inhibition of viral replication. Furthermore, these unique CD8+ T cells can respond to immune checkpoint blockade (ICB) therapy. In this review, we discuss the functions of these CD8+ T cells as well as the translation of findings into viable HIV treatment and cure strategies.
    Keywords:  B-cell follicle; CXCR5+ CD8+ T cell; HIV-1; HIV-specific CD8+ T cells; immunotherapy
    DOI:  https://doi.org/10.3389/fmicb.2022.998058
  22. Sci Immunol. 2022 Dec 09. 7(78): eadd3075
    Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells.
    Marco Künzli, Stephen D O'Flanagan, Madeleine LaRue, Poulami Talukder, Thamotharampillai Dileepan, J Michael Stolley, Andrew G Soerens, Clare F Quarnstrom, Sathi Wijeyesinghe, Yanqi Ye, Justine S McPartlan, Jason S Mitchell, Christian W Mandl, Richard Vile, Marc K Jenkins, Rafi Ahmed, Vaiva Vezys, Jasdave S Chahal, David Masopust.
      Respiratory tract resident memory T cells (TRM), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory TRM. We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron-based nanoparticles. Here, we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influenced influenza-specific cell-mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 TRM in the lung and draining lymph nodes. Contralateral, compared with ipsilateral, intramuscular boosting broadened the distribution of lymph node TRM and T follicular helper cells but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory but augmented distribution to the respiratory mucosa. Combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung TRM. Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung TRM that can be further expanded by an additional intranasal immunization.
    DOI:  https://doi.org/10.1126/sciimmunol.add3075
  23. Nat Commun. 2022 Dec 02. 13(1): 7431
    Protein-Peptide Turnover Profiling reveals the order of PTM addition and removal during protein maturation.
    Henrik M Hammarén, Eva-Maria Geissen, Clement M Potel, Martin Beck, Mikhail M Savitski.
      Post-translational modifications (PTMs) regulate various aspects of protein function, including degradation. Mass spectrometric methods relying on pulsed metabolic labeling are popular to quantify turnover rates on a proteome-wide scale. Such data have traditionally been interpreted in the context of protein proteolytic stability. Here, we combine theoretical kinetic modeling with experimental pulsed stable isotope labeling of amino acids in cell culture (pSILAC) for the study of protein phosphorylation. We demonstrate that metabolic labeling combined with PTM-specific enrichment does not measure effects of PTMs on protein stability. Rather, it reveals the relative order of PTM addition and removal along a protein's lifetime-a fundamentally different metric. This is due to interconversion of the measured proteoform species. Using this framework, we identify temporal phosphorylation sites on cell cycle-specific factors and protein complex assembly intermediates. Our results thus allow tying PTMs to the age of the modified proteins.
    DOI:  https://doi.org/10.1038/s41467-022-35054-2
  24. Nat Commun. 2022 Nov 30. 13(1): 7391
    Self-cleaving guide RNAs enable pharmacological selection of precise gene editing events in vivo.
    Amita Tiyaboonchai, Anne Vonada, Jeffrey Posey, Carl Pelz, Leslie Wakefield, Markus Grompe.
      Expression of guide RNAs in the CRISPR/Cas9 system typically requires the use of RNA polymerase III promoters, which are not cell-type specific. Flanking the gRNA with self-cleaving ribozyme motifs to create a self-cleaving gRNA overcomes this limitation. Here, we use self-cleaving gRNAs to create drug-selectable gene editing events in specific hepatocyte loci. A recombinant Adeno Associated Virus vector targeting the Albumin locus with a promoterless self-cleaving gRNA to create drug resistance is linked in cis with the therapeutic transgene. Gene expression of both are dependent on homologous recombination into the target locus. In vivo drug selection for the precisely edited hepatocytes allows >30-fold expansion of gene-edited cells and results in therapeutic levels of a human Factor 9 transgene. Importantly, self-cleaving gRNA expression is also achieved after targeting weak hepatocyte genes. We conclude that self-cleaving gRNAs are a powerful system to enable cell-type specific in vivo drug resistance for therapeutic gene editing applications.
    DOI:  https://doi.org/10.1038/s41467-022-35097-5
  25. Nat Commun. 2022 Nov 28. 13(1): 7323
    Secreted EMC10 is upregulated in human obesity and its neutralizing antibody prevents diet-induced obesity in mice.
    Xuanchun Wang, Yanliang Li, Guifen Qiang, Kaihua Wang, Jiarong Dai, Maximilian McCann, Marcos D Munoz, Victoria Gil, Yifei Yu, Shengxian Li, Zhihong Yang, Shanshan Xu, Jose Cordoba-Chacon, Dario F De Jesus, Bei Sun, Kuangyang Chen, Yahao Wang, Xiaoxia Liu, Qing Miao, Linuo Zhou, Renming Hu, Qiang Ding, Rohit N Kulkarni, Daming Gao, Matthias Blüher, Chong Wee Liew.
      Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a poorly characterized secreted protein of largely unknown physiological function. Here we demonstrate that scEMC10 is upregulated in people with obesity and is positively associated with insulin resistance. Consistent with a causal role for scEMC10 in obesity, Emc10-/- mice are resistant to diet-induced obesity due to an increase in energy expenditure, while scEMC10 overexpression decreases energy expenditure, thus promoting obesity in mouse. Furthermore, neutralization of circulating scEMC10 using a monoclonal antibody reduces body weight and enhances insulin sensitivity in obese mice. Mechanistically, we provide evidence that scEMC10 can be transported into cells where it binds to the catalytic subunit of PKA and inhibits its stimulatory action on CREB while ablation of EMC10 promotes thermogenesis in adipocytes via activation of the PKA signalling pathway and its downstream targets. Taken together, our data identify scEMC10 as a circulating inhibitor of thermogenesis and a potential therapeutic target for obesity and its cardiometabolic complications.
    DOI:  https://doi.org/10.1038/s41467-022-34259-9
  26. Nat Commun. 2022 Dec 02. 13(1): 7414
    Nuclear localization of mitochondrial TCA cycle enzymes modulates pluripotency via histone acetylation.
    Wei Li, Qi Long, Hao Wu, Yanshuang Zhou, Lifan Duan, Hao Yuan, Yingzhe Ding, Yile Huang, Yi Wu, Jinyu Huang, Delong Liu, Baodan Chen, Jian Zhang, Juntao Qi, Shiwei Du, Linpeng Li, Yang Liu, Zifeng Ruan, Zihuang Liu, Zichao Liu, Yifan Zhao, Jianghuan Lu, Junwei Wang, Wai-Yee Chan, Xingguo Liu.
      Pluripotent stem cells hold great promise in regenerative medicine and developmental biology studies. Mitochondrial metabolites, including tricarboxylic acid (TCA) cycle intermediates, have been reported to play critical roles in pluripotency. Here we show that TCA cycle enzymes including Pdha1, Pcb, Aco2, Cs, Idh3a, Ogdh, Sdha and Mdh2 are translocated to the nucleus during somatic cell reprogramming, primed-to-naive transition and totipotency acquisition. The nuclear-localized TCA cycle enzymes Pdha1, Pcb, Aco2, Cs, Idh3a promote somatic cell reprogramming and primed-to-naive transition. In addition, nuclear-localized TCA cycle enzymes, particularly nuclear-targeted Pdha1, facilitate the 2-cell program in pluripotent stem cells. Mechanistically, nuclear Pdha1 increases the acetyl-CoA and metabolite pool in the nucleus, leading to chromatin remodeling at pluripotency genes by enhancing histone H3 acetylation. Our results reveal an important role of mitochondrial TCA cycle enzymes in the epigenetic regulation of pluripotency that constitutes a mitochondria-to-nucleus retrograde signaling mode in different states of pluripotent acquisition.
    DOI:  https://doi.org/10.1038/s41467-022-35199-0
  27. J Immunol. 2022 Nov 23. pii: ji2200194. [Epub ahead of print]
    Follicular CD8+ T Cells Are Elevated in HIV Infection and Induce PD-L1 on B Cells.
    Laura E Martínez, Javier Ibarrondo, Yu Guo, Manuel L Penichet, Marta Epeldegui.
      Follicular CD8+CXCR5+ T cells are a specialized CD8+ T cell subset with unique follicular-homing capabilities that have been reported to display effector functions in viral immunity, tumor immunity, and autoimmunity. CD8+CXCR5+ T cells exhibit B cell helper functions and express CD40L, ICOS, programmed cell death protein 1 (PD-1), and BCL-6, the transcriptional regulator of CD4+CXCR5+ T follicular helper cells and of germinal center B cells. HIV is known to be sequestered in lymphoid follicles, and CD8+CXCR5+ T cell frequency is a marker for disease severity, given that HIV-infected patients with lower numbers of circulating CD8+CXCR5+ T cells display lower CD4+ T cell counts. Likewise, several groups have reported a direct correlation between the quantity of CD8+CXCR5+ T cells and suppression of HIV viral load. In this study, we observed elevated absolute numbers of CD8+CXCR5+ and CD8+CXCR5+BCL-6+PD-1+ T cells in the blood of HIV-infected participants of the Multicenter AIDS Cohort Study. We further demonstrated in vitro that activated human CD8+CXCR5+ T cells isolated from peripheral blood and tonsil from healthy donors show increased CD40L expression and induce the production of PD ligand 1 (PD-L1)+IgG+ B cells. Moreover, absolute numbers of CD8+CXCR5+ T cells significantly and positively correlated with numbers of PD-L1+ B cells found in blood of HIV-infected individuals. Altogether, these results show that activated CD8+CXCR5+ T cells have the ability to activate B cells and increase the percentage of PD-L1+ and PD-L1+IgG+ B cells, which provides insights into the early events of B cell activation and differentiation and may play a role in disease progression and lymphomagenesis in HIV-infected individuals.
    DOI:  https://doi.org/10.4049/jimmunol.2200194
  28. Eur J Immunol. 2022 Dec 02.
    Toll-like receptors control the accumulation of neutrophils in lymph nodes that expand CD4+ T cells during experimental autoimmune encephalomyelitis.
    Ping Shen, Madlen Rother, Ulrik Stervbo, Vicky Lampropoulou, Elisabeth Calderon-Gomez, Toralf Roch, Ellen Hilgenberg, Steffi Ries, Anja A Kühl, Luc Jouneau, Pierre Boudinot, Simon Fillatreau.
      Toll-like receptors (TLR) control the activation of dendritic cells that prime CD4+ T cells in draining lymph nodes, where these T cells then undergo massive clonal expansion. The mechanisms controlling this clonal T cell expansion are poorly defined. Using the CD4+ T cell-mediated disease experimental autoimmune encephalomyelitis (EAE), we show here that this process is markedly suppressed when TLR9 signaling is increased, without noticeably affecting the transcriptome of primed T cells, indicating a purely quantitative effect on CD4+ T cell expansion. Addressing the underpinning mechanisms revealed that CD4+ T cell expansion was preceded and depended on the accumulation of neutrophils in lymph nodes a few days after immunization. Underlying the importance of this immune regulation pathway, blocking neutrophil accumulation in lymph nodes by treating mice with a TLR9 agonist inhibited EAE progression in mice with defects in regulatory T cells or regulatory B cells, which otherwise developed a severe chronic disease. Collectively, this study demonstrates the key role of neutrophils in the quantitative regulation of antigen-specific CD4+ T cell expansion in lymph nodes, and the counter-regulatory role of TLR signaling in this process. This article is protected by copyright. All rights reserved.
    Keywords:  CD4+ T cells; EAE; Toll-like receptor; autoimmunity; neutrophil
    DOI:  https://doi.org/10.1002/eji.202250059
  29. Nat Commun. 2022 Dec 02. 13(1): 7435
    Structures of the eukaryotic ribosome and its translational states in situ.
    Patrick C Hoffmann, Jan Philipp Kreysing, Iskander Khusainov, Maarten W Tuijtel, Sonja Welsch, Martin Beck.
      Ribosomes translate genetic information into primary structure. During translation, various cofactors transiently bind to the ribosome that undergoes prominent conformational and structural changes. Different translational states of ribosomes have been well characterized in vitro. However, to which extent the known translational states are representative of the native situation inside cells has thus far only been addressed in prokaryotes. Here, we apply cryo-electron tomography to cryo-FIB milled Dictyostelium discoideum cells combined with subtomogram averaging and classification. We obtain an in situ structure that is locally resolved up to 3 Angstrom, the distribution of eukaryotic ribosome translational states, and unique arrangement of rRNA expansion segments. Our work demonstrates the use of in situ structural biology techniques for identifying distinct ribosome states within the cellular environment.
    DOI:  https://doi.org/10.1038/s41467-022-34997-w
  30. Sci Immunol. 2022 Dec 09. 7(78): eadf9316
    Fishing with autoantibodies nets a gut bacteria that drives arthritis.
    Rachael A Clark.
      A fecal bacterial strain cross-reacts with rheumatoid arthritis autoantibodies, stimulates CD4+ T cells, and induces joint disease in mice.
    DOI:  https://doi.org/10.1126/sciimmunol.adf9316
  31. Nat Commun. 2022 Nov 30. 13(1): 7373
    Membrane-mediated protein interactions drive membrane protein organization.
    Yining Jiang, Batiste Thienpont, Vinay Sapuru, Richard K Hite, Jeremy S Dittman, James N Sturgis, Simon Scheuring.
      The plasma membrane's main constituents, i.e., phospholipids and membrane proteins, are known to be organized in lipid-protein functional domains and supercomplexes. No active membrane-intrinsic process is known to establish membrane organization. Thus, the interplay of thermal fluctuations and the biophysical determinants of membrane-mediated protein interactions must be considered to understand membrane protein organization. Here, we used high-speed atomic force microscopy and kinetic and membrane elastic theory to investigate the behavior of a model membrane protein in oligomerization and assembly in controlled lipid environments. We find that membrane hydrophobic mismatch modulates oligomerization and assembly energetics, and 2D organization. Our experimental and theoretical frameworks reveal how membrane organization can emerge from Brownian diffusion and a minimal set of physical properties of the membrane constituents.
    DOI:  https://doi.org/10.1038/s41467-022-35202-8
  32. Nature. 2022 Nov 28.
    Structures of the holo CRISPR RNA-guided transposon integration complex.
    Jung-Un Park, Amy Wei-Lun Tsai, Alexandrea N Rizo, Vinh H Truong, Tristan X Wellner, Richard D Schargel, Elizabeth H Kellogg.
      CRISPR-associated transposons (CAST) are programmable mobile genetic elements that insert large DNA cargo using an RNA-guided mechanism1-3. CAST elements contain multiple conserved genes, including: a CRISPR effector (Cas12k or Cascade), a AAA+ regulator (TnsC), a transposase (TnsA/TnsB), and a target site associated factor (TniQ). These components are thought to cooperatively integrate DNA via formation of a multisubunit transposition integration complex (transpososome). Here we reconstitute the approximately 1 MDa type V-K CAST transpososome from Scytonema hofmannii (ShCAST) and determined the structure to near-atomic resolution (3.5 Å) using single particle cryo-EM. Transpososome architecture reveals modular association between components. Cas12k forms a complex with ribosomal subunit S15 and TniQ, stabilizing formation of a full R-loop. TnsC has dedicated interaction interfaces with TniQ and TnsB. Interestingly, we observe novel TnsC-TnsB interactions at the C-terminal face of TnsC, which contribute to stimulation of ATPase activity. Although the TnsC oligomeric assembly slightly deviates from the helical configuration found in isolation, the TnsC-bound target DNA conformation differs dramatically in the transpososome. As a consequence, TnsC makes new protein-DNA interactions throughout the transpososome that are important for transposition activity. Finally, we discover two distinct transpososome populations which differ in their DNA contacts near TniQ. This suggests that associations with the CRISPR effector can be flexible. This ShCAST transpososome structure significantly enhances our understanding of CAST transposition systems and suggests avenues for improving CAST transposition for precision genome-editing applications.
    DOI:  https://doi.org/10.1038/s41586-022-05573-5
  33. Nat Commun. 2022 Nov 28. 13(1): 7329
    Gene activation guided by nascent RNA-bound transcription factors.
    Ying Liang, Haiyue Xu, Tao Cheng, Yujuan Fu, Hanwei Huang, Wenchang Qian, Junyan Wang, Yuenan Zhou, Pengxu Qian, Yafei Yin, Pengfei Xu, Wei Zou, Baohui Chen.
      Technologies for gene activation are valuable tools for the study of gene functions and have a wide range of potential applications in bioengineering and medicine. In contrast to existing methods based on recruiting transcriptional modulators via DNA-binding proteins, we developed a strategy termed Narta (nascent RNA-guided transcriptional activation) to achieve gene activation by recruiting artificial transcription factors (aTFs) to transcription sites through nascent RNAs of the target gene. Using Narta, we demonstrate robust activation of a broad range of exogenous and endogenous genes in various cell types, including zebrafish embryos, mouse and human cells. Importantly, the activation is reversible, tunable and specific. Moreover, Narta provides better activation potency of some expressed genes than CRISPRa and, when used in combination with CRISPRa, has an enhancing effect on gene activation. Quantitative imaging illustrated that nascent RNA-directed aTFs could induce the high-density assembly of coactivators at transcription sites, which may explain the larger transcriptional burst size induced by Narta. Overall, our work expands the gene activation toolbox for biomedical research.
    DOI:  https://doi.org/10.1038/s41467-022-35041-7
  34. Nat Commun. 2022 Dec 02. 13(1): 7446
    Discrete LAT condensates encode antigen information from single pMHC:TCR binding events.
    Darren B McAffee, Mark K O'Dair, Jenny J Lin, Shalini T Low-Nam, Kiera B Wilhelm, Sungi Kim, Shumpei Morita, Jay T Groves.
      LAT assembly into a two-dimensional protein condensate is a prominent feature of antigen discrimination by T cells. Here, we use single-molecule imaging techniques to resolve the spatial position and temporal duration of each pMHC:TCR molecular binding event while simultaneously monitoring LAT condensation at the membrane. An individual binding event is sufficient to trigger a LAT condensate, which is self-limiting, and neither its size nor lifetime is correlated with the duration of the originating pMHC:TCR binding event. Only the probability of the LAT condensate forming is related to the pMHC:TCR binding dwell time. LAT condenses abruptly, but after an extended delay from the originating binding event. A LAT mutation that facilitates phosphorylation at the PLC-γ1 recruitment site shortens the delay time to LAT condensation and alters T cell antigen specificity. These results identify a function for the LAT protein condensation phase transition in setting antigen discrimination thresholds in T cells.
    DOI:  https://doi.org/10.1038/s41467-022-35093-9
  35. Nat Commun. 2022 Nov 26. 13(1): 7283
    CryoEM structure and assembly mechanism of a bacterial virus genome gatekeeper.
    Igor Orlov, Stéphane Roche, Sandrine Brasilès, Natalya Lukoyanova, Marie-Christine Vaney, Paulo Tavares, Elena V Orlova.
      Numerous viruses package their dsDNA genome into preformed capsids through a portal gatekeeper that is subsequently closed. We report the structure of the DNA gatekeeper complex of bacteriophage SPP1 (gp612gp1512gp166) in the post-DNA packaging state at 2.7 Å resolution obtained by single particle cryo-electron microscopy. Comparison of the native SPP1 complex with assembly-naïve structures of individual components uncovered the complex program of conformational changes leading to its assembly. After DNA packaging, gp15 binds via its C-terminus to the gp6 oligomer positioning gp15 subunits for oligomerization. Gp15 refolds its inner loops creating an intersubunit β-barrel that establishes different types of contacts with six gp16 subunits. Gp16 binding and oligomerization is accompanied by folding of helices that close the portal channel to keep the viral genome inside the capsid. This mechanism of assembly has broad functional and evolutionary implications for viruses of the prokaryotic tailed viruses-herpesviruses lineage.
    DOI:  https://doi.org/10.1038/s41467-022-34999-8
  36. Nat Commun. 2022 Dec 01. 13(1): 7405
    A self-powered ingestible wireless biosensing system for real-time in situ monitoring of gastrointestinal tract metabolites.
    Ernesto De la Paz, Nikhil Harsha Maganti, Alexander Trifonov, Itthipon Jeerapan, Kuldeep Mahato, Lu Yin, Thitaporn Sonsa-Ard, Nicolas Ma, Won Jung, Ryan Burns, Amir Zarrinpar, Joseph Wang, Patrick P Mercier.
      Information related to the diverse and dynamic metabolite composition of the small intestine is crucial for the diagnosis and treatment of various diseases. However, our current understanding of the physiochemical dynamics of metabolic processes within the small intestine is limited due to the lack of in situ access to the intestinal environment. Here, we report a demonstration of a battery-free ingestible biosensing system for monitoring metabolites in the small intestine. As a proof of concept, we monitor the intestinal glucose dynamics on a porcine model. Battery-free operation is achieved through a self-powered glucose biofuel cell/biosensor integrated into a circuit that performs energy harvesting, biosensing, and wireless telemetry via a power-to-frequency conversion scheme using magnetic human body communication. Such long-term biochemical analysis could potentially provide critical information regarding the complex and dynamic small intestine metabolic profiles.
    DOI:  https://doi.org/10.1038/s41467-022-35074-y
  37. Nat Commun. 2022 Nov 29. 13(1): 7345
    IL6 supports long-term expansion of hepatocytes in vitro.
    Ren Guo, Mengmeng Jiang, Gang Wang, Bing Li, Xiaohui Jia, Yan Ai, Shanshan Chen, Peilan Tang, Aijie Liu, Qianting Yuan, Xin Xie.
      Hepatocytes are very difficult to expand in vitro. A few studies have demonstrated that chemical cocktails with growth factors or Wnt ligands can support long-term expansion of hepatocytes via dedifferentiation. However, the culture conditions are complex, and clonal expansion of hepatic progenitors with full differentiation capacity are rarely reported. Here, we discover IL6, combined with EGF and HGF, promotes long-term expansion (>30 passages in ~150 days with theoretical expansion of ~1035 times) of primary mouse hepatocytes in vitro in simple 2D culture, by converting hepatocytes into induced hepatic progenitor cells (iHPCs), which maintain the capacity of differentiation into hepatocytes. IL6 also supports the establishment of single hepatocyte-derived iHPC clones. The summation of the downstream STAT3, ERK and AKT pathways induces a number of transcription factors which support rapid growth. This physiological and simple way may provide ideas for culturing previously difficult-to-culture cell types and support their future applications.
    DOI:  https://doi.org/10.1038/s41467-022-35167-8
  38. Sci Adv. 2022 Dec 02. 8(48): eadc9657
    Phosphofructokinase P fine-tunes T regulatory cell metabolism, function, and stability in systemic autoimmunity.
    Marc Scherlinger, Wenliang Pan, Ryo Hisada, Afroditi Boulougoura, Nobuya Yoshida, Milena Vukelic, Masataka Umeda, Suzanne Krishfield, Maria G Tsokos, George C Tsokos.
      Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by defective regulatory T (Treg) cells. Here, we demonstrate that a T cell-specific deletion of calcium/calmodulin-dependent protein kinase 4 (CaMK4) improves disease in B6.lpr lupus-prone mice and expands Treg cells. Mechanistically, CaMK4 phosphorylates the glycolysis rate-limiting enzyme 6-phosphofructokinase, platelet type (PFKP) and promotes aerobic glycolysis, while its end product fructose-1,6-biphosphate suppresses oxidative metabolism. In Treg cells, a CRISPR-Cas9-enabled Pfkp deletion recapitulated the metabolism of Camk4-/- Treg cells and improved their function and stability in vitro and in vivo. In SLE CD4+ T cells, PFKP enzymatic activity correlated with SLE disease activity and pharmacologic inhibition of CaMK4-normalized PFKP activity, leading to enhanced Treg cell function. In conclusion, we provide molecular insights in the defective metabolism and function of Treg cells in SLE and identify PFKP as a target to fine-tune Treg cell metabolism and thereby restore their function.
    DOI:  https://doi.org/10.1126/sciadv.adc9657
  39. Nat Commun. 2022 Nov 28. 13(1): 7159
    PCGF1-PRC1 links chromatin repression with DNA replication during hematopoietic cell lineage commitment.
    Junichiro Takano, Shinsuke Ito, Yixing Dong, Jafar Sharif, Yaeko Nakajima-Takagi, Taichi Umeyama, Yong-Woon Han, Kyoichi Isono, Takashi Kondo, Yusuke Iizuka, Tomohiro Miyai, Yoko Koseki, Mika Ikegaya, Mizuki Sakihara, Manabu Nakayama, Osamu Ohara, Yoshinori Hasegawa, Kosuke Hashimoto, Erik Arner, Robert J Klose, Atsushi Iwama, Haruhiko Koseki, Tomokatsu Ikawa.
      Polycomb group proteins (PcG), polycomb repressive complexes 1 and 2 (PRC1 and 2), repress lineage inappropriate genes during development to maintain proper cellular identities. It has been recognized that PRC1 localizes at the replication fork, however, the precise functions of PRC1 during DNA replication are elusive. Here, we reveal that a variant PRC1 containing PCGF1 (PCGF1-PRC1) prevents overloading of activators and chromatin remodeling factors on nascent DNA and thereby mediates proper deposition of nucleosomes and correct downstream chromatin configurations in hematopoietic stem and progenitor cells (HSPCs). This function of PCGF1-PRC1 in turn facilitates PRC2-mediated repression of target genes such as Hmga2 and restricts premature myeloid differentiation. PCGF1-PRC1, therefore, maintains the differentiation potential of HSPCs by linking proper nucleosome configuration at the replication fork with PcG-mediated gene silencing to ensure life-long hematopoiesis.
    DOI:  https://doi.org/10.1038/s41467-022-34856-8
  40. J Cell Biol. 2023 Feb 06. pii: e202102119. [Epub ahead of print]222(2):
    GSK3α phosphorylates dynamin-2 to promote GLUT4 endocytosis in muscle cells.
    Jessica Laiman, Yen-Jung Hsu, Julie Loh, Wei-Chun Tang, Mei-Chun Chuang, Hui-Kang Liu, Wei-Shun Yang, Bi-Chang Chen, Lee-Ming Chuang, Yi-Cheng Chang, Ya-Wen Liu.
      Insulin-stimulated translocation of glucose transporter 4 (GLUT4) to plasma membrane of skeletal muscle is critical for postprandial glucose uptake; however, whether the internalization of GLUT4 is also regulated by insulin signaling remains unclear. Here, we discover that the activity of dynamin-2 (Dyn2) in catalyzing GLUT4 endocytosis is negatively regulated by insulin signaling in muscle cells. Mechanistically, the fission activity of Dyn2 is inhibited by binding with the SH3 domain of Bin1. In the absence of insulin, GSK3α phosphorylates Dyn2 to relieve the inhibition of Bin1 and promotes endocytosis. Conversely, insulin signaling inactivates GSK3α and leads to attenuated GLUT4 internalization. Furthermore, the isoform-specific pharmacological inhibition of GSK3α significantly improves insulin sensitivity and glucose tolerance in diet-induced insulin-resistant mice. Together, we identify a new role of GSK3α in insulin-stimulated glucose disposal by regulating Dyn2-mediated GLUT4 endocytosis in muscle cells. These results highlight the isoform-specific function of GSK3α on membrane trafficking and its potential as a therapeutic target for metabolic disorders.
    DOI:  https://doi.org/10.1083/jcb.202102119
  41. Nat Immunol. 2022 Dec 01.
    Fungal sensing by dectin-1 directs the non-pathogenic polarization of TH17 cells through balanced type I IFN responses in human DCs.
    Sonja I Gringhuis, Tanja M Kaptein, Ester B M Remmerswaal, Agata Drewniak, Brigitte A Wevers, Bart Theelen, Geert R A M D'Haens, Teun Boekhout, Teunis B H Geijtenbeek.
      The non-pathogenic TH17 subset of helper T cells clears fungal infections, whereas pathogenic TH17 cells cause inflammation and tissue damage; however, the mechanisms controlling these distinct responses remain unclear. Here we found that fungi sensing by the C-type lectin dectin-1 in human dendritic cells (DCs) directed the polarization of non-pathogenic TH17 cells. Dectin-1 signaling triggered transient and intermediate expression of interferon (IFN)-β in DCs, which was mediated by the opposed activities of transcription factors IRF1 and IRF5. IFN-β-induced signaling led to integrin αvβ8 expression directly and to the release of the active form of the cytokine transforming growth factor (TGF)-β indirectly. Uncontrolled IFN-β responses as a result of IRF1 deficiency induced high expression of the IFN-stimulated gene BST2 in DCs and restrained TGF-β activation. Active TGF-β was required for polarization of non-pathogenic TH17 cells, whereas pathogenic TH17 cells developed in the absence of active TGF-β. Thus, dectin-1-mediated modulation of type I IFN responses allowed TGF-β activation and non-pathogenic TH17 cell development during fungal infections in humans.
    DOI:  https://doi.org/10.1038/s41590-022-01348-2
  42. Trends Endocrinol Metab. 2022 Nov 23. pii: S1043-2760(22)00199-0. [Epub ahead of print]
    Mitochondrial copper in human genetic disorders.
    Natalie M Garza, Abhinav B Swaminathan, Krishna P Maremanda, Mohammad Zulkifli, Vishal M Gohil.
      Copper is an essential micronutrient that serves as a cofactor for enzymes involved in diverse physiological processes, including mitochondrial energy generation. Copper enters cells through a dedicated copper transporter and is distributed to intracellular cuproenzymes by copper chaperones. Mitochondria are critical copper-utilizing organelles that harbor an essential cuproenzyme cytochrome c oxidase, which powers energy production. Mutations in copper transporters and chaperones that perturb mitochondrial copper homeostasis result in fatal genetic disorders. Recent studies have uncovered the therapeutic potential of elesclomol, a copper ionophore, for the treatment of copper deficiency disorders such as Menkes disease. Here we review the role of copper in mitochondrial energy metabolism in the context of human diseases and highlight the recent developments in copper therapeutics.
    Keywords:  Menkes disease; Wilson disease; copper; elesclomol; mitochondria; mitochondrial disease
    DOI:  https://doi.org/10.1016/j.tem.2022.11.001
  43. Nat Commun. 2022 Nov 26. 13(1): 7291
    Structural basis for lipid and copper regulation of the ABC transporter MsbA.
    Jixing Lyu, Chang Liu, Tianqi Zhang, Samantha Schrecke, Nicklaus P Elam, Charles Packianathan, Georg K A Hochberg, David Russell, Minglei Zhao, Arthur Laganowsky.
      A critical step in lipopolysaccharide (LPS) biogenesis involves flipping lipooligosaccharide, an LPS precursor, from the cytoplasmic to the periplasmic leaflet of the inner membrane, an operation carried out by the ATP-binding cassette transporter MsbA. Although LPS binding to the inner cavity of MsbA is well established, the selectivity of MsbA-lipid interactions at other site(s) remains poorly understood. Here we use native mass spectrometry (MS) to characterize MsbA-lipid interactions and guide structural studies. We show the transporter co-purifies with copper(II) and metal binding modulates protein-lipid interactions. A 2.15 Å resolution structure of an N-terminal region of MsbA in complex with copper(II) is presented, revealing a structure reminiscent of the GHK peptide, a high-affinity copper(II) chelator. Our results demonstrate conformation-dependent lipid binding affinities, particularly for the LPS-precursor, 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo)2-lipid A (KDL). We report a 3.6 Å-resolution structure of MsbA trapped in an open, outward-facing conformation with adenosine 5'-diphosphate and vanadate, revealing a distinct KDL binding site, wherein the lipid forms extensive interactions with the transporter. Additional studies provide evidence that the exterior KDL binding site is conserved and a positive allosteric modulator of ATPase activity, serving as a feedforward activation mechanism to couple transporter activity with LPS biosynthesis.
    DOI:  https://doi.org/10.1038/s41467-022-34905-2
  44. Proc Natl Acad Sci U S A. 2022 Dec 06. 119(49): e2212548119
    Early microbial exposure shapes adult immunity by altering CD8+ T cell development.
    Cybelle Tabilas, David S Iu, Ciarán W P Daly, Kristel J Yee Mon, Arnold Reynaldi, Samantha P Wesnak, Jennifer K Grenier, Miles P Davenport, Norah L Smith, Andrew Grimson, Brian D Rudd.
      Microbial exposure during development can elicit long-lasting effects on the health of an individual. However, how microbial exposure in early life leads to permanent changes in the immune system is unknown. Here, we show that the microbial environment alters the set point for immune susceptibility by altering the developmental architecture of the CD8+ T cell compartment. In particular, early microbial exposure results in the preferential expansion of highly responsive fetal-derived CD8+ T cells that persist into adulthood and provide the host with enhanced immune protection against intracellular pathogens. Interestingly, microbial education of fetal-derived CD8+ T cells occurs during thymic development rather than in the periphery and involves the acquisition of a more effector-like epigenetic program. Collectively, our results provide a conceptual framework for understanding how microbial colonization in early life leads to lifelong changes in the immune system.
    Keywords:  CD8+ T cells; developmental layering; developmental origins of adult health and disease; immune training; pet-shop dirty mouse model
    DOI:  https://doi.org/10.1073/pnas.2212548119
  45. Nat Commun. 2022 Dec 02. 13(1): 7449
    Immunosuppressive biomaterial-based therapeutic vaccine to treat multiple sclerosis via re-establishing immune tolerance.
    Thanh Loc Nguyen, Youngjin Choi, Jihye Im, Hyunsu Shin, Ngoc Man Phan, Min Kyung Kim, Seung Woo Choi, Jaeyun Kim.
      Current therapies for autoimmune diseases, such as multiple sclerosis (MS), induce broad suppression of the immune system, potentially promoting opportunistic infections. Here, we report an immunosuppressive biomaterial-based therapeutic vaccine carrying self-antigen and tolerance-inducing inorganic nanoparticles to treat experimental autoimmune encephalomyelitis (EAE), a mouse model mimicking human MS. Immunization with self-antigen-loaded mesoporous nanoparticles generates Foxp3+ regulatory T-cells in spleen and systemic immune tolerance in EAE mice, reducing central nervous system-infiltrating antigen-presenting cells (APCs) and autoreactive CD4+ T-cells. Introducing reactive oxygen species (ROS)-scavenging cerium oxide nanoparticles (CeNP) to self-antigen-loaded nanovaccine additionally suppresses activation of APCs and enhances antigen-specific immune tolerance, inducing recovery in mice from complete paralysis at the late, chronic stage of EAE, which shows similarity to chronic human MS. This study clearly shows that the ROS-scavenging capability of catalytic inorganic nanoparticles could be utilized to enhance tolerogenic features in APCs, leading to antigen-specific immune tolerance, which could be exploited in treating MS.
    DOI:  https://doi.org/10.1038/s41467-022-35263-9
  46. Cell Regen. 2022 Dec 01. 11(1): 38
    Mitochondrial fragmentation and ROS signaling in wound response and repair.
    Shiqi Xu, Shiyao Li, Mikael Bjorklund, Suhong Xu.
      Mitochondria are organelles that serve numerous critical cellular functions, including energy production, Ca2+ homeostasis, redox signaling, and metabolism. These functions are intimately linked to mitochondrial morphology, which is highly dynamic and capable of rapid and transient changes to alter cellular functions in response to environmental cues and cellular demands. Mitochondrial morphology and activity are critical for various physiological processes, including wound healing. In mammals, wound healing is a complex process that requires coordinated function of multiple cell types and progresses in partially overlapping but distinct stages: hemostasis and inflammation, cell proliferation and migration, and tissue remodeling. The repair process at the single-cell level forms the basis for wound healing and regeneration in tissues. Recent findings reveal that mitochondria fulfill the intensive energy demand for wound repair and aid wound closure by cytoskeleton remodeling via morphological changes and mitochondrial reactive oxygen species (mtROS) signaling. In this review, we will mainly elucidate how wounding induces changes in mitochondrial morphology and activity and how these changes, in turn, contribute to cellular wound response and repair.
    Keywords:  FZO-1; MFN-1/2; MIRO-1; Membrane repair; Mitochondrial dynamic; Mitochondrial fragmentation; Plasma membrane; Reactive oxygen species
    DOI:  https://doi.org/10.1186/s13619-022-00141-8
  47. Cell Discov. 2022 Nov 29. 8(1): 128
    Loss of function of CMPK2 causes mitochondria deficiency and brain calcification.
    Miao Zhao, Hui-Zhen Su, Yi-Heng Zeng, Yuan Sun, Xin-Xin Guo, Yun-Lu Li, Chong Wang, Zhi-Yuan Zhao, Xue-Jing Huang, Kai-Jun Lin, Zi-Ling Ye, Bi-Wei Lin, Shunyan Hong, Jitan Zheng, Yao-Bin Liu, Xiang-Ping Yao, Dehao Yang, Ying-Qian Lu, Hai-Zhu Chen, Erwei Zuo, Guang Yang, Hong-Tao Wang, Chen-Wei Huang, Xiao-Hong Lin, Zhidong Cen, Lu-Lu Lai, Yan-Ke Zhang, Xi Li, Tianmin Lai, Jingjing Lin, Dan-Dan Zuo, Min-Ting Lin, Chia-Wei Liou, Qing-Xia Kong, Chuan-Zhu Yan, Zhi-Qi Xiong, Ning Wang, Wei Luo, Cui-Ping Zhao, Xuewen Cheng, Wan-Jin Chen.
      Brain calcification is a critical aging-associated pathology and can cause multifaceted neurological symptoms. Cerebral phosphate homeostasis dysregulation, blood-brain barrier defects, and immune dysregulation have been implicated as major pathological processes in familial brain calcification (FBC). Here, we analyzed two brain calcification families and identified calcification co-segregated biallelic variants in the CMPK2 gene that disrupt mitochondrial functions. Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) isolated from these patients showed impaired mitochondria-associated metabolism pathways. In situ hybridization and single-cell RNA sequencing revealed robust Cmpk2 expression in neurons and vascular endothelial cells (vECs), two cell types with high energy expenditure in the brain. The neurons in Cmpk2-knockout (KO) mice have fewer mitochondrial DNA copies, down-regulated mitochondrial proteins, reduced ATP production, and elevated intracellular inorganic phosphate (Pi) level, recapitulating the mitochondrial dysfunction observed in the PBMCs isolated from the FBC patients. Morphologically, the cristae architecture of the Cmpk2-KO murine neurons was also impaired. Notably, calcification developed in a progressive manner in the homozygous Cmpk2-KO mice thalamus region as well as in the Cmpk2-knock-in mice bearing the patient mutation, thus phenocopying the calcification pathology observed in the patients. Together, our study identifies biallelic variants of CMPK2 as novel genetic factors for FBC; and demonstrates how CMPK2 deficiency alters mitochondrial structures and functions, thereby highlighting the mitochondria dysregulation as a critical pathogenic mechanism underlying brain calcification.
    DOI:  https://doi.org/10.1038/s41421-022-00475-2
  48. Commun Biol. 2022 Nov 27. 5(1): 1301
    Single-cell multiomics reveals the complexity of TGFβ signalling to chromatin in iPSC-derived kidney organoids.
    Jessica L Davis, Ciaran Kennedy, Shane Clerkin, Niall J Treacy, Thomas Dodd, Catherine Moss, Alison Murphy, Derek P Brazil, Gerard Cagney, Dermot F Brougham, Rabi Murad, Darren Finlay, Kristiina Vuori, John Crean.
      TGFβ1 plays a regulatory role in the determination of renal cell fate and the progression of renal fibrosis. Here we show an association between SMAD3 and the histone methyltransferase, EZH2, during cell differentiation; ChIP-seq revealed that SMAD3 and EZH2 co-occupy the genome in iPSCs and in iPSC-derived nephron progenitors. Through integration of single cell gene expression and epigenome profiling, we identified de novo ACTA2+ve/POSTN+ve myofibroblasts in kidney organoids treated with TGFβ1, characterised by increased SMAD3-dependent cis chromatin accessibility and gene expression associated with fibroblast activation. We have identified fibrosis-associated regulons characterised by enrichment of SMAD3, AP1, the ETS family of transcription factors, and NUAK1, CREB3L1, and RARG, corresponding to enriched motifs at accessible loci identified by scATACseq. Treatment with the EZH2 specific inhibitor GSK343, blocked SMAD3-dependent cis co-accessibility and inhibited myofibroblast activation. This mechanism, through which TGFβ signals directly to chromatin, represents a critical determinant of fibrotic, differentiated states.
    DOI:  https://doi.org/10.1038/s42003-022-04264-1
  49. Nat Immunol. 2022 Dec 02.
    Anti-fungal role for type I IFN as dectin-1 triggers non-pathogenic TH17 cell development.
      
    DOI:  https://doi.org/10.1038/s41590-022-01357-1
  50. Nat Commun. 2022 Nov 28. 13(1): 7330
    SOTIP is a versatile method for microenvironment modeling with spatial omics data.
    Zhiyuan Yuan, Yisi Li, Minglei Shi, Fan Yang, Juntao Gao, Jianhua Yao, Michael Q Zhang.
      The rapidly developing spatial omics generated datasets with diverse scales and modalities. However, most existing methods focus on modeling dynamics of single cells while ignore microenvironments (MEs). Here we present SOTIP (Spatial Omics mulTIPle-task analysis), a versatile method incorporating MEs and their interrelationships into a unified graph. Based on this graph, spatial heterogeneity quantification, spatial domain identification, differential microenvironment analysis, and other downstream tasks can be performed. We validate each module's accuracy, robustness, scalability and interpretability on various spatial omics datasets. In two independent mouse cerebral cortex spatial transcriptomics datasets, we reveal a gradient spatial heterogeneity pattern strongly correlated with the cortical depth. In human triple-negative breast cancer spatial proteomics datasets, we identify molecular polarizations and MEs associated with different patient survivals. Overall, by modeling biologically explainable MEs, SOTIP outperforms state-of-art methods and provides some perspectives for spatial omics data exploration and interpretation.
    DOI:  https://doi.org/10.1038/s41467-022-34867-5
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