bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–05–14
forty-five papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis.
  2. Space to meditate.
  3. FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors.
  4. Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function.
  5. Lysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis by promoting the degradation of CDC42 in mice.
  6. Mitotic clustering of pulverized chromosomes from micronuclei.
  7. Anatomical and functional maturation of the mid-gestation human enteric nervous system.
  8. Comparative analysis of cell-cell communication at single-cell resolution.
  9. Triggered Golgi membrane enrichment promotes PtdIns(4,5)P2 generation for plasma membrane repair.
  10. A draft human pangenome reference.
  11. Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes.
  12. A prime editor mouse to model a broad spectrum of somatic mutations in vivo.
  13. Metaphocytes are IL-22BP-producing cells regulated by ETS transcription factor Spic and essential for zebrafish barrier immunity.
  14. Genetically prolonged beige fat in male mice confers long-lasting metabolic health.
  15. Interpreting non-coding disease-associated human variants using single-cell epigenomics.
  16. meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans.
  17. Task-specific modulation of corticospinal neuron activity during motor learning in mice.
  18. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.
  19. Bacterial NLR-related proteins protect against phage.
  20. Human metabolome variation along the upper intestinal tract.
  21. Lipid flipping in the omega-3 fatty-acid transporter.
  22. Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface.
  23. In situ architecture of the ER-mitochondria encounter structure.
  24. The histone H2B ubiquitination regulator Wac is essential for plasma cell differentiation.
  25. Diet-mediated constitutive induction of novel IL-4+ ILC2 cells maintains intestinal homeostasis in mice.
  26. Cell-selective proteomics segregates pancreatic cancer subtypes by extracellular proteins in tumors and circulation.
  27. Anti-human-TIGIT agonistic antibody ameliorates autoimmune diseases by inhibiting Tfh and Tph cells and enhancing Treg cells.
  28. Organ-specific aging and the risk of chronic diseases.
  29. PLIN2-induced ectopic lipid accumulation promotes muscle ageing in gregarious locusts.
  30. How nociceptors shape dendritic cell responses.
  31. Croquemort elicits activation of the immune deficiency pathway in ticks.
  32. Phage display sequencing reveals that genetic, environmental, and intrinsic factors influence variation of human antibody epitope repertoire.
  33. Artificial Hsp104-mediated systems for re-localizing protein aggregates.
  34. The PECAn image and statistical analysis pipeline identifies Minute cell competition genes and features.
  35. 'Persistent germinal center responses: slow-growing trees bear the best fruits'.
  36. Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries.
  37. Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis.
  38. Neonatal immune challenge poses a sex-specific risk for epigenetic microglial reprogramming and behavioral impairment.
  39. Roles of long non-coding RNAs in plant immunity.
  40. Plasmodium falciparum has evolved multiple mechanisms to hijack human immunoglobulin M.
  41. Macrophages show up in style when Th2 lymphocytes organize their homecoming.
  42. Genome-wide profiling of prime editor off-target sites in vitro and in vivo using PE-tag.
  43. CD4+ T cell memory.
  44. Centralspindlin proteins Pavarotti and Tumbleweed along with WASH regulate nuclear envelope budding.
  45. Human embryo science: can the world's regulators keep pace?
  1. Nat Commun. 2023 May 11. 14(1): 2715
    UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis.
    Tao Zhang, Na Zhang, Jing Xing, Shuhua Zhang, Yulu Chen, Daichao Xu, Jinyang Gu.
      Hepatocyte apoptosis plays an essential role in the progression of nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms underlying hepatocyte apoptosis remain unclear. Here, we identify UDP-glucose 6-dehydrogenase (UGDH) as a suppressor of NASH-associated liver damage by inhibiting RIPK1 kinase-dependent hepatocyte apoptosis. UGDH is progressively reduced in proportion to NASH severity. UGDH absence from hepatocytes hastens the development of liver damage in male mice with NASH, which is suppressed by RIPK1 kinase-dead knockin mutation. Mechanistically, UGDH suppresses RIPK1 by converting UDP-glucose to UDP-glucuronate, the latter directly binds to the kinase domain of RIPK1 and inhibits its activation. Recovering UDP-glucuronate levels, even after the onset of NASH, improved liver damage. Our findings reveal a role for UGDH and UDP-glucuronate in NASH pathogenesis and uncover a mechanism by which UDP-glucuronate controls hepatocyte apoptosis by targeting RIPK1 kinase, and suggest UDP-glucuronate metabolism as a feasible target for more specific treatment of NASH-associated liver damage.
    DOI:  https://doi.org/10.1038/s41467-023-38371-2
  2. Science. 2023 May 12. 380(6645): 662
    Space to meditate.
    Alex Hubert.
      
    DOI:  https://doi.org/10.1126/science.adc3352
  3. EMBO J. 2023 May 10. e112767
    FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors.
    Giang Thanh Nguyen-Dien, Keri-Lyn Kozul, Yi Cui, Brendan Townsend, Prajakta Gosavi Kulkarni, Soo Siang Ooi, Antonio Marzio, Nissa Carrodus, Steven Zuryn, Michele Pagano, Robert G Parton, Michael Lazarou, S Sean Millard, Robert W Taylor, Brett M Collins, Mathew Jk Jones, Julia K Pagan.
      To maintain both mitochondrial quality and quantity, cells selectively remove damaged or excessive mitochondria through mitophagy, which is a specialised form of autophagy. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation and mitochondrial damage. However, the mechanisms that govern the removal of specific dysfunctional mitochondria under steady-state conditions to fine-tune mitochondrial content are not well understood. Here, we report that SCFFBXL4 , an SKP1/CUL1/F-box protein ubiquitin ligase complex, localises to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that the pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13) do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism whereby FBXL4 actively suppresses mitophagy by preventing NIX and BNIP3 accumulation. We propose that the dysregulation of NIX and BNIP3 turnover causes excessive basal mitophagy in FBXL4-associated mtDNA depletion syndrome.
    Keywords:  BNIP3; FBXL4; NIX/BNIP3L; mitochondria; mitophagy
    DOI:  https://doi.org/10.15252/embj.2022112767
  4. Nat Cell Biol. 2023 May 08.
    Creatine kinase B suppresses ferroptosis by phosphorylating GPX4 through a moonlighting function.
    Ke Wu, Meisi Yan, Tong Liu, Zheng Wang, Yuran Duan, Yan Xia, Guimei Ji, Yuli Shen, Lei Wang, Lin Li, Peixiang Zheng, Bofei Dong, Qingang Wu, Liwei Xiao, Xueying Yang, Haochen Shen, Ting Wen, Jingjing Zhang, Jinfeng Yi, Yuhan Deng, Xu Qian, Leina Ma, Jing Fang, Qin Zhou, Zhimin Lu, Daqian Xu.
      Activation of receptor protein kinases is prevalent in various cancers with unknown impact on ferroptosis. Here we demonstrated that AKT activated by insulin-like growth factor 1 receptor signalling phosphorylates creatine kinase B (CKB) T133, reduces metabolic activity of CKB and increases CKB binding to glutathione peroxidase 4 (GPX4). Importantly, CKB acts as a protein kinase and phosphorylates GPX4 S104. This phosphorylation prevents HSC70 binding to GPX4, thereby abrogating the GPX4 degradation regulated by chaperone-mediated autophagy, alleviating ferroptosis and promoting tumour growth in mice. In addition, the levels of GPX4 are positively correlated with the phosphorylation levels of CKB T133 and GPX4 S104 in human hepatocellular carcinoma specimens and associated with poor prognosis of patients with hepatocellular carcinoma. These findings reveal a critical mechanism by which tumour cells counteract ferroptosis by non-metabolic function of CKB-enhanced GPX4 stability and underscore the potential to target the protein kinase activity of CKB for cancer treatment.
    DOI:  https://doi.org/10.1038/s41556-023-01133-9
  5. Nat Commun. 2023 May 08. 14(1): 2654
    Lysosomal-associated protein transmembrane 5 ameliorates non-alcoholic steatohepatitis by promoting the degradation of CDC42 in mice.
    Lang Jiang, Jing Zhao, Qin Yang, Mei Li, Hao Liu, Xiaoyue Xiao, Song Tian, Sha Hu, Zhen Liu, Peiwen Yang, Manhua Chen, Ping Ye, Jiahong Xia.
      Non-alcoholic steatohepatitis (NASH) has received great attention due to its high incidence. Here, we show that lysosomal-associated protein transmembrane 5 (LAPTM5) is associated with NASH progression through extensive bioinformatical analysis. The protein level of LAPTM5 bears a negative correlation with NAS score. Moreover, LAPTM5 degradation is mediated through its ubiquitination modification by the E3 ubquitin ligase NEDD4L. Discovered by experiments conducted on male mice, hepatocyte-specific depletion of Laptm5 exacerbates mouse NASH symptoms. In contrast, Laptm5 overexpression in hepatocytes exerts diametrically opposite effects. Mechanistically, LAPTM5 interacts with CDC42 and promotes its degradation through a lysosome-dependent manner under the stimulation of palmitic acid, thus inhibiting activation of the mitogen-activated protein kinase signaling pathway. Finally, adenovirus-mediated hepatic Laptm5 overexpression ameliorates aforementioned symptoms in NASH models.
    DOI:  https://doi.org/10.1038/s41467-023-37908-9
  6. Nature. 2023 May 10.
    Mitotic clustering of pulverized chromosomes from micronuclei.
    Yu-Fen Lin, Qing Hu, Alice Mazzagatti, Jose Espejo Valle-Inclán, Elizabeth G Maurais, Rashmi Dahiya, Alison Guyer, Jacob T Sanders, Justin L Engel, Giaochau Nguyen, Daniel Bronder, Samuel F Bakhoum, Isidro Cortés-Ciriano, Peter Ly.
      Complex genome rearrangements can be generated by the catastrophic pulverization of missegregated chromosomes trapped within micronuclei through a process known as chromothripsis1-5. As each chromosome contains a single centromere, it remains unclear how acentric fragments derived from shattered chromosomes are inherited between daughter cells during mitosis6. Here we tracked micronucleated chromosomes with live-cell imaging and show that acentric fragments cluster in close spatial proximity throughout mitosis for asymmetric inheritance by a single daughter cell. Mechanistically, the CIP2A-TOPBP1 complex prematurely associates with DNA lesions within ruptured micronuclei during interphase, which poises pulverized chromosomes for clustering upon mitotic entry. Inactivation of CIP2A-TOPBP1 caused acentric fragments to disperse throughout the mitotic cytoplasm, stochastically partition into the nucleus of both daughter cells and aberrantly misaccumulate as cytoplasmic DNA. Mitotic clustering facilitates the reassembly of acentric fragments into rearranged chromosomes lacking the extensive DNA copy-number losses that are characteristic of canonical chromothripsis. Comprehensive analysis of pan-cancer genomes revealed clusters of DNA copy-number-neutral rearrangements-termed balanced chromothripsis-across diverse tumour types resulting in the acquisition of known cancer driver events. Thus, distinct patterns of chromothripsis can be explained by the spatial clustering of pulverized chromosomes from micronuclei.
    DOI:  https://doi.org/10.1038/s41586-023-05974-0
  7. Nat Commun. 2023 May 09. 14(1): 2680
    Anatomical and functional maturation of the mid-gestation human enteric nervous system.
    Lori B Dershowitz, Li Li, Anca M Pasca, Julia A Kaltschmidt.
      Immature gastrointestinal motility impedes preterm infant survival. The enteric nervous system controls gastrointestinal motility, yet it is unknown when the human enteric nervous system matures enough to carry out vital functions. Here we demonstrate that the second trimester human fetal enteric nervous system takes on a striped organization akin to the embryonic mouse. Further, we perform ex vivo functional assays of human fetal tissue and find that human fetal gastrointestinal motility matures in a similar progression to embryonic mouse gastrointestinal motility. Together, this provides critical knowledge, which facilitates comparisons with common animal models to advance translational disease investigations and testing of pharmacological agents to enhance gastrointestinal motility in prematurity.
    DOI:  https://doi.org/10.1038/s41467-023-38293-z
  8. Nat Biotechnol. 2023 May 11.
    Comparative analysis of cell-cell communication at single-cell resolution.
    Aaron J Wilk, Alex K Shalek, Susan Holmes, Catherine A Blish.
      Inference of cell-cell communication from single-cell RNA sequencing data is a powerful technique to uncover intercellular communication pathways, yet existing methods perform this analysis at the level of the cell type or cluster, discarding single-cell-level information. Here we present Scriabin, a flexible and scalable framework for comparative analysis of cell-cell communication at single-cell resolution that is performed without cell aggregation or downsampling. We use multiple published atlas-scale datasets, genetic perturbation screens and direct experimental validation to show that Scriabin accurately recovers expected cell-cell communication edges and identifies communication networks that can be obscured by agglomerative methods. Additionally, we use spatial transcriptomic data to show that Scriabin can uncover spatial features of interaction from dissociated data alone. Finally, we demonstrate applications to longitudinal datasets to follow communication pathways operating between timepoints. Our approach represents a broadly applicable strategy to reveal the full structure of niche-phenotype relationships in health and disease.
    DOI:  https://doi.org/10.1038/s41587-023-01782-z
  9. J Cell Biol. 2023 Aug 07. pii: e202303017. [Epub ahead of print]222(8):
    Triggered Golgi membrane enrichment promotes PtdIns(4,5)P2 generation for plasma membrane repair.
    Xinan Meng, Chandra Sugiarto Wijaya, Qingfang Shao, Suhong Xu.
      The maintenance of plasma membrane integrity and a capacity for efficiently repairing damaged membranes are essential for cell survival. Large-scale wounding depletes various membrane components at the wound sites, including phosphatidylinositols, yet little is known about how phosphatidylinositols are generated after depletion. Here, working with our in vivo C. elegans epidermal cell wounding model, we discovered phosphatidylinositol 4-phosphate (PtdIns4P) accumulation and local phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] generation at the wound site. We found that PtdIns(4,5)P2 generation depends on the delivery of PtdIns4P, PI4K, and PI4P 5-kinase PPK-1. In addition, we show that wounding triggers enrichment of the Golgi membrane to the wound site, and that is required for membrane repair. Moreover, genetic and pharmacological inhibitor experiments support that the Golgi membrane provides the PtdIns4P for PtdIns(4,5)P2 generation at the wounds. Our findings demonstrate how the Golgi apparatus facilitates membrane repair in response to wounding and offers a valuable perspective on cellular survival mechanisms upon mechanical stress in a physiological context.
    DOI:  https://doi.org/10.1083/jcb.202303017
  10. Nature. 2023 May;617(7960): 312-324
    A draft human pangenome reference.
    Wen-Wei Liao, Mobin Asri, Jana Ebler, Daniel Doerr, Marina Haukness, Glenn Hickey, Shuangjia Lu, Julian K Lucas, Jean Monlong, Haley J Abel, Silvia Buonaiuto, Xian H Chang, Haoyu Cheng, Justin Chu, Vincenza Colonna, Jordan M Eizenga, Xiaowen Feng, Christian Fischer, Robert S Fulton, Shilpa Garg, Cristian Groza, Andrea Guarracino, William T Harvey, Simon Heumos, Kerstin Howe, Miten Jain, Tsung-Yu Lu, Charles Markello, Fergal J Martin, Matthew W Mitchell, Katherine M Munson, Moses Njagi Mwaniki, Adam M Novak, Hugh E Olsen, Trevor Pesout, David Porubsky, Pjotr Prins, Jonas A Sibbesen, Jouni Sirén, Chad Tomlinson, Flavia Villani, Mitchell R Vollger, Lucinda L Antonacci-Fulton, Gunjan Baid, Carl A Baker, Anastasiya Belyaeva, Konstantinos Billis, Andrew Carroll, Pi-Chuan Chang, Sarah Cody, Daniel E Cook, Robert M Cook-Deegan, Omar E Cornejo, Mark Diekhans, Peter Ebert, Susan Fairley, Olivier Fedrigo, Adam L Felsenfeld, Giulio Formenti, Adam Frankish, Yan Gao, Nanibaa' A Garrison, Carlos Garcia Giron, Richard E Green, Leanne Haggerty, Kendra Hoekzema, Thibaut Hourlier, Hanlee P Ji, Eimear E Kenny, Barbara A Koenig, Alexey Kolesnikov, Jan O Korbel, Jennifer Kordosky, Sergey Koren, HoJoon Lee, Alexandra P Lewis, Hugo Magalhães, Santiago Marco-Sola, Pierre Marijon, Ann McCartney, Jennifer McDaniel, Jacquelyn Mountcastle, Maria Nattestad, Sergey Nurk, Nathan D Olson, Alice B Popejoy, Daniela Puiu, Mikko Rautiainen, Allison A Regier, Arang Rhie, Samuel Sacco, Ashley D Sanders, Valerie A Schneider, Baergen I Schultz, Kishwar Shafin, Michael W Smith, Heidi J Sofia, Ahmad N Abou Tayoun, Françoise Thibaud-Nissen, Francesca Floriana Tricomi, Justin Wagner, Brian Walenz, Jonathan M D Wood, Aleksey V Zimin, Guillaume Bourque, Mark J P Chaisson, Paul Flicek, Adam M Phillippy, Justin M Zook, Evan E Eichler, David Haussler, Ting Wang, Erich D Jarvis, Karen H Miga, Erik Garrison, Tobias Marschall, Ira M Hall, Heng Li, Benedict Paten.
      Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.
    DOI:  https://doi.org/10.1038/s41586-023-05896-x
  11. Nat Commun. 2023 May 11. 14(1): 2712
    Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes.
    Chirag Nepal, Jesper B Andersen.
      Transcriptional regulation is commonly governed by alternative promoters. However, the regulatory architecture in alternative and reference promoters, and how they differ, remains elusive. In 100 CAGE-seq libraries from hepatocellular carcinoma patients, here we annotate 4083 alternative promoters in 2926 multi-promoter genes, which are largely undetected in normal livers. These genes are enriched in oncogenic processes and predominantly show association with overall survival. Alternative promoters are narrow nucleosome depleted regions, CpG island depleted, and enriched for tissue-specific transcription factors. Globally tumors lose DNA methylation. We show hierarchical retention of intragenic DNA methylation with CG-poor regions rapidly losing methylation, while CG-rich regions retain it, a process mediated by differential SETD2, H3K36me3, DNMT3B, and TET1 binding. This mechanism is validated in SETD2 knockdown cells and SETD2-mutated patients. Selective DNA methylation loss in CG-poor regions makes the chromatin accessible for alternative transcription. We show alternative promoters can control tumor transcriptomes and their regulatory architecture.
    DOI:  https://doi.org/10.1038/s41467-023-38272-4
  12. Nat Biotechnol. 2023 May 11.
    A prime editor mouse to model a broad spectrum of somatic mutations in vivo.
    Zackery A Ely, Nicolas Mathey-Andrews, Santiago Naranjo, Samuel I Gould, Kim L Mercer, Gregory A Newby, Christina M Cabana, William M Rideout, Grissel Cervantes Jaramillo, Jennifer M Khirallah, Katie Holland, Peyton B Randolph, William A Freed-Pastor, Jessie R Davis, Zachary Kulstad, Peter M K Westcott, Lin Lin, Andrew V Anzalone, Brendan L Horton, Nimisha B Pattada, Sean-Luc Shanahan, Zhongfeng Ye, Stefani Spranger, Qiaobing Xu, Francisco J Sánchez-Rivera, David R Liu, Tyler Jacks.
      Genetically engineered mouse models only capture a small fraction of the genetic lesions that drive human cancer. Current CRISPR-Cas9 models can expand this fraction but are limited by their reliance on error-prone DNA repair. Here we develop a system for in vivo prime editing by encoding a Cre-inducible prime editor in the mouse germline. This model allows rapid, precise engineering of a wide range of mutations in cell lines and organoids derived from primary tissues, including a clinically relevant Kras mutation associated with drug resistance and Trp53 hotspot mutations commonly observed in pancreatic cancer. With this system, we demonstrate somatic prime editing in vivo using lipid nanoparticles, and we model lung and pancreatic cancer through viral delivery of prime editing guide RNAs or orthotopic transplantation of prime-edited organoids. We believe that this approach will accelerate functional studies of cancer-associated mutations and complex genetic combinations that are challenging to construct with traditional models.
    DOI:  https://doi.org/10.1038/s41587-023-01783-y
  13. Cell Rep. 2023 May 05. pii: S2211-1247(23)00494-1. [Epub ahead of print]42(5): 112483
    Metaphocytes are IL-22BP-producing cells regulated by ETS transcription factor Spic and essential for zebrafish barrier immunity.
    Changlong Zhao, Yunbo Li, Jinlin Tang, Qiuxia Zhou, Xi Lin, Zilong Wen.
      Metaphocytes are tissue-resident macrophage (TRM)/dendritic cell (DC)-like cells of non-hematopoietic origin in zebrafish barrier tissues. One remarkable property of metaphocytes is their ability to capture soluble antigens from the external environment via transepithelial protrusions, a unique function manifested by specialized subpopulations of the TRMs/DCs in mammal barrier tissues. Yet, how metaphocytes acquire myeloid-like cell properties from non-hematopoietic precursors and how they regulate barrier immunity remains unknown. Here, we show that metaphocytes are in situ generated from local progenitors guided by the ETS transcription factor Spic, the deficiency of which results in the absence of metaphocytes. We further document that metaphocytes are the major IL-22BP-producing cells, and the depletion of metaphocytes causes dysregulated barrier immunity that resembles the phenotype of IL-22BP-deficient mice. These findings reveal the ontogeny, development, and function of metaphocytes in zebrafish, which facilitates our understanding of the nature and function of the mammalian TRM/DC counterparts.
    Keywords:  CP: Immunology
    DOI:  https://doi.org/10.1016/j.celrep.2023.112483
  14. Nat Commun. 2023 May 12. 14(1): 2731
    Genetically prolonged beige fat in male mice confers long-lasting metabolic health.
    Ruifan Wu, Jooman Park, Yanyu Qian, Zuoxiao Shi, Ruoci Hu, Yexian Yuan, Shaolei Xiong, Zilai Wang, Gege Yan, Sang-Ging Ong, Qing Song, Zhenyuan Song, Abeer M Mahmoud, Pingwen Xu, Congcong He, Robert W Arpke, Michael Kyba, Gang Shu, Qingyan Jiang, Yuwei Jiang.
      A potential therapeutic target to curb obesity and diabetes is thermogenic beige adipocytes. However, beige adipocytes quickly transition into white adipocytes upon removing stimuli. Here, we define the critical role of cyclin dependent kinase inhibitor 2A (Cdkn2a) as a molecular pedal for the beige-to-white transition. Beige adipocytes lacking Cdkn2a exhibit prolonged lifespan, and male mice confer long-term metabolic protection from diet-induced obesity, along with enhanced energy expenditure and improved glucose tolerance. Mechanistically, Cdkn2a promotes the expression and activity of beclin 1 (BECN1) by directly binding to its mRNA and its negative regulator BCL2 like 1 (BCL2L1), activating autophagy and accelerating the beige-to-white transition. Reactivating autophagy by pharmacological or genetic methods abolishes beige adipocyte maintenance induced by Cdkn2a ablation. Furthermore, hyperactive BECN1 alone accelerates the beige-to-white transition in mice and human. Notably, both Cdkn2a and Becn1 exhibit striking positive correlations with adiposity. Hence, blocking Cdkn2a-mediated BECN1 activity holds therapeutic potential to sustain beige adipocytes in treating obesity and related metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-023-38471-z
  15. Nat Rev Genet. 2023 May 09.
    Interpreting non-coding disease-associated human variants using single-cell epigenomics.
    Kyle J Gaulton, Sebastian Preissl, Bing Ren.
      Genome-wide association studies (GWAS) have linked hundreds of thousands of sequence variants in the human genome to common traits and diseases. However, translating this knowledge into a mechanistic understanding of disease-relevant biology remains challenging, largely because such variants are predominantly in non-protein-coding sequences that still lack functional annotation at cell-type resolution. Recent advances in single-cell epigenomics assays have enabled the generation of cell type-, subtype- and state-resolved maps of the epigenome in heterogeneous human tissues. These maps have facilitated cell type-specific annotation of candidate cis-regulatory elements and their gene targets in the human genome, enhancing our ability to interpret the genetic basis of common traits and diseases.
    DOI:  https://doi.org/10.1038/s41576-023-00598-6
  16. Nat Commun. 2023 May 11. 14(1): 2711
    meQTL mapping in the GENOA study reveals genetic determinants of DNA methylation in African Americans.
    Lulu Shang, Wei Zhao, Yi Zhe Wang, Zheng Li, Jerome J Choi, Minjung Kho, Thomas H Mosley, Sharon L R Kardia, Jennifer A Smith, Xiang Zhou.
      Identifying genetic variants that are associated with variation in DNA methylation, an analysis commonly referred to as methylation quantitative trait locus (meQTL) mapping, is an important first step towards understanding the genetic architecture underlying epigenetic variation. Most existing meQTL mapping studies have focused on individuals of European ancestry and are underrepresented in other populations, with a particular absence of large studies in populations with African ancestry. We fill this critical knowledge gap by performing a large-scale cis-meQTL mapping study in 961 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We identify a total of 4,565,687 cis-acting meQTLs in 320,965 meCpGs. We find that 45% of meCpGs harbor multiple independent meQTLs, suggesting potential polygenic genetic architecture underlying methylation variation. A large percentage of the cis-meQTLs also colocalize with cis-expression QTLs (eQTLs) in the same population. Importantly, the identified cis-meQTLs explain a substantial proportion (median = 24.6%) of methylation variation. In addition, the cis-meQTL associated CpG sites mediate a substantial proportion (median = 24.9%) of SNP effects underlying gene expression. Overall, our results represent an important step toward revealing the co-regulation of methylation and gene expression, facilitating the functional interpretation of epigenetic and gene regulation underlying common diseases in African Americans.
    DOI:  https://doi.org/10.1038/s41467-023-37961-4
  17. Nat Commun. 2023 May 11. 14(1): 2708
    Task-specific modulation of corticospinal neuron activity during motor learning in mice.
    Najet Serradj, Francesca Marino, Yunuen Moreno-López, Amanda Bernstein, Sydney Agger, Marwa Soliman, Andrew Sloan, Edmund Hollis.
      Motor skill learning relies on the plasticity of the primary motor cortex as task acquisition drives cortical motor network remodeling. Large-scale cortical remodeling of evoked motor outputs occurs during the learning of corticospinal-dependent prehension behavior, but not simple, non-dexterous tasks. Here we determine the response of corticospinal neurons to two distinct motor training paradigms and assess the role of corticospinal neurons in the execution of a task requiring precise modulation of forelimb movement and one that does not. In vivo calcium imaging in mice revealed temporal coding of corticospinal activity coincident with the development of precise prehension movements, but not more simplistic movement patterns. Transection of the corticospinal tract and optogenetic regulation of corticospinal activity show the necessity for patterned corticospinal network activity in the execution of precise movements but not simplistic ones. Our findings reveal a critical role for corticospinal network modulation in the learning and execution of precise motor movements.
    DOI:  https://doi.org/10.1038/s41467-023-38418-4
  18. Nature. 2023 May 10.
    Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.
    Luis A Rojas, Zachary Sethna, Kevin C Soares, Cristina Olcese, Nan Pang, Erin Patterson, Jayon Lihm, Nicholas Ceglia, Pablo Guasp, Alexander Chu, Rebecca Yu, Adrienne Kaya Chandra, Theresa Waters, Jennifer Ruan, Masataka Amisaki, Abderezak Zebboudj, Zagaa Odgerel, George Payne, Evelyna Derhovanessian, Felicitas Müller, Ina Rhee, Mahesh Yadav, Anton Dobrin, Michel Sadelain, Marta Łuksza, Noah Cohen, Laura Tang, Olca Basturk, Mithat Gönen, Seth Katz, Richard Kinh Do, Andrew S Epstein, Parisa Momtaz, Wungki Park, Ryan Sugarman, Anna M Varghese, Elizabeth Won, Avni Desai, Alice C Wei, Michael I D'Angelica, T Peter Kingham, Ira Mellman, Taha Merghoub, Jedd D Wolchok, Ugur Sahin, Özlem Türeci, Benjamin D Greenbaum, William R Jarnagin, Jeffrey Drebin, Eileen M O'Reilly, Vinod P Balachandran.
      Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.
    DOI:  https://doi.org/10.1038/s41586-023-06063-y
  19. Cell. 2023 May 03. pii: S0092-8674(23)00411-7. [Epub ahead of print]
    Bacterial NLR-related proteins protect against phage.
    Emily M Kibby, Amy N Conte, A Maxwell Burroughs, Toni A Nagy, Jose A Vargas, Lindsay A Whalen, L Aravind, Aaron T Whiteley.
      Bacteria use a wide range of immune pathways to counter phage infection. A subset of these genes shares homology with components of eukaryotic immune systems, suggesting that eukaryotes horizontally acquired certain innate immune genes from bacteria. Here, we show that proteins containing a NACHT module, the central feature of the animal nucleotide-binding domain and leucine-rich repeat containing gene family (NLRs), are found in bacteria and defend against phages. NACHT proteins are widespread in bacteria, provide immunity against both DNA and RNA phages, and display the characteristic C-terminal sensor, central NACHT, and N-terminal effector modules. Some bacterial NACHT proteins have domain architectures similar to the human NLRs that are critical components of inflammasomes. Human disease-associated NLR mutations that cause stimulus-independent activation of the inflammasome also activate bacterial NACHT proteins, supporting a shared signaling mechanism. This work establishes that NACHT module-containing proteins are ancient mediators of innate immunity across the tree of life.
    Keywords:  NACHT; NLR; STAND; bacteriophage; inflammasome; innate immunity; phage defense
    DOI:  https://doi.org/10.1016/j.cell.2023.04.015
  20. Nat Metab. 2023 May 10.
    Human metabolome variation along the upper intestinal tract.
    Jacob Folz, Rebecca Neal Culver, Juan Montes Morales, Jessica Grembi, George Triadafilopoulos, David A Relman, Kerwyn Casey Huang, Dari Shalon, Oliver Fiehn.
      Most processing of the human diet occurs in the small intestine. Metabolites in the small intestine originate from host secretions, plus the ingested exposome1 and microbial transformations. Here we probe the spatiotemporal variation of upper intestinal luminal contents during routine daily digestion in 15 healthy male and female participants. For this, we use a non-invasive, ingestible sampling device to collect and analyse 274 intestinal samples and 60 corresponding stool homogenates by combining five mass spectrometry assays2,3 and 16S rRNA sequencing. We identify 1,909 metabolites, including sulfonolipids and fatty acid esters of hydroxy fatty acids (FAHFA) lipids. We observe that stool and intestinal metabolomes differ dramatically. Food metabolites display trends in dietary biomarkers, unexpected increases in dicarboxylic acids along the intestinal tract and a positive association between luminal keto acids and fruit intake. Diet-derived and microbially linked metabolites account for the largest inter-individual differences. Notably, two individuals who had taken antibiotics within 6 months before sampling show large variation in levels of bioactive FAHFAs and sulfonolipids and other microbially related metabolites. From inter-individual variation, we identify Blautia species as a candidate to be involved in FAHFA metabolism. In conclusion, non-invasive, in vivo sampling of the human small intestine and ascending colon under physiological conditions reveals links between diet, host and microbial metabolism.
    DOI:  https://doi.org/10.1038/s42255-023-00777-z
  21. Nat Commun. 2023 May 08. 14(1): 2571
    Lipid flipping in the omega-3 fatty-acid transporter.
    Chi Nguyen, Hsiang-Ting Lei, Louis Tung Faat Lai, Marc J Gallenito, Xuelang Mu, Doreen Matthies, Tamir Gonen.
      Mfsd2a is the transporter for docosahexaenoic acid (DHA), an omega-3 fatty acid, across the blood brain barrier (BBB). Defects in Mfsd2a are linked to ailments from behavioral and motor dysfunctions to microcephaly. Mfsd2a transports long-chain unsaturated fatty-acids, including DHA and α-linolenic acid (ALA), that are attached to the zwitterionic lysophosphatidylcholine (LPC) headgroup. Even with the recently determined structures of Mfsd2a, the molecular details of how this transporter performs the energetically unfavorable task of translocating and flipping lysolipids across the lipid bilayer remains unclear. Here, we report five single-particle cryo-EM structures of Danio rerio Mfsd2a (drMfsd2a): in the inward-open conformation in the ligand-free state and displaying lipid-like densities modeled as ALA-LPC at four distinct positions. These Mfsd2a snapshots detail the flipping mechanism for lipid-LPC from outer to inner membrane leaflet and release for membrane integration on the cytoplasmic side. These results also map Mfsd2a mutants that disrupt lipid-LPC transport and are associated with disease.
    DOI:  https://doi.org/10.1038/s41467-023-37702-7
  22. Nat Commun. 2023 May 09. 14(1): 2683
    Zinc homeostasis governed by Golgi-resident ZnT family members regulates ERp44-mediated proteostasis at the ER-Golgi interface.
    Yuta Amagai, Momo Yamada, Toshiyuki Kowada, Tomomi Watanabe, Yuyin Du, Rong Liu, Satoshi Naramoto, Satoshi Watanabe, Junko Kyozuka, Tiziana Anelli, Tiziana Tempio, Roberto Sitia, Shin Mizukami, Kenji Inaba.
      Many secretory enzymes acquire essential zinc ions (Zn2+) in the Golgi complex. ERp44, a chaperone operating in the early secretory pathway, also binds Zn2+ to regulate its client binding and release for the control of protein traffic and homeostasis. Notably, three membrane transporter complexes, ZnT4, ZnT5/ZnT6 and ZnT7, import Zn2+ into the Golgi lumen in exchange with protons. To identify their specific roles, we here perform quantitative Zn2+ imaging using super-resolution microscopy and Zn2+-probes targeted in specific Golgi subregions. Systematic ZnT-knockdowns reveal that ZnT4, ZnT5/ZnT6 and ZnT7 regulate labile Zn2+ concentration at the distal, medial, and proximal Golgi, respectively, consistent with their localization. Time-course imaging of cells undergoing synchronized secretory protein traffic and functional assays demonstrates that ZnT-mediated Zn2+ fluxes tune the localization, trafficking, and client-retrieval activity of ERp44. Altogether, this study provides deep mechanistic insights into how ZnTs control Zn2+ homeostasis and ERp44-mediated proteostasis along the early secretory pathway.
    DOI:  https://doi.org/10.1038/s41467-023-38397-6
  23. Nature. 2023 May 10.
    In situ architecture of the ER-mitochondria encounter structure.
    Michael R Wozny, Andrea Di Luca, Dustin R Morado, Andrea Picco, Rasha Khaddaj, Pablo Campomanes, Lazar Ivanović, Patrick C Hoffmann, Elizabeth A Miller, Stefano Vanni, Wanda Kukulski.
      The endoplasmic reticulum and mitochondria are main hubs of eukaryotic membrane biogenesis that rely on lipid exchange via membrane contact sites1-3, but the underpinning mechanisms remain poorly understood. In yeast, tethering and lipid transfer between the two organelles is mediated by the endoplasmic reticulum-mitochondria encounter structure (ERMES), a four-subunit complex of unresolved stoichiometry and architecture4-6. Here we determined the molecular organization of ERMES within Saccharomyces cerevisiae cells using integrative structural biology by combining quantitative live imaging, cryo-correlative microscopy, subtomogram averaging and molecular modelling. We found that ERMES assembles into approximately 25 discrete bridge-like complexes distributed irregularly across a contact site. Each bridge consists of three synaptotagmin-like mitochondrial lipid binding protein domains oriented in a zig-zag arrangement. Our molecular model of ERMES reveals a pathway for lipids. These findings resolve the in situ supramolecular architecture of a major inter-organelle lipid transfer machinery and provide a basis for the mechanistic understanding of lipid fluxes in eukaryotic cells.
    DOI:  https://doi.org/10.1038/s41586-023-06050-3
  24. FEBS Lett. 2023 May 12.
    The histone H2B ubiquitination regulator Wac is essential for plasma cell differentiation.
    Yuxing Li, Gui-Xin Ruan, Wenjing Chen, Hengjun Huang, Rui Zhang, Jing Wang, Yu Ouyang, Zhijian Zhu, Limin Meng, Ruisi Wang, Jianxin Huo, Shengli Xu, Xijun Ou.
      Naïve B cells become activated and differentiate into antibody-secreting plasma cells (PCs) when encountering antigens. Here, we reveal that the WW domain-containing adapter protein with coiled-coil (Wac), which is important for histone H2B ubiquitination (ubH2B), is essential for PC differentiation. We demonstrate that B cell-specific Wac knockout mice have severely compromised T cell-dependent and -independent antibody responses. PC differentiation is drastically compromised despite undisturbed germinal center B cell responses in the mutant mice. We also observed a significant reduction in global ubH2B in Wac-deficient B cells, which is correlated with downregulated expression of some genes critical for cell metabolism. Thus, our findings demonstrate an essential role of Wac-mediated ubH2B in PC differentiation and shed light on the epigenetic mechanisms underlying this process.
    Keywords:  B cell; H2B ubiquitination; Wac; antibody response; plasma cell
    DOI:  https://doi.org/10.1002/1873-3468.14633
  25. J Exp Med. 2023 Aug 07. pii: e20221773. [Epub ahead of print]220(8):
    Diet-mediated constitutive induction of novel IL-4+ ILC2 cells maintains intestinal homeostasis in mice.
    Wanlin Cui, Yuji Nagano, Satoru Morita, Takeshi Tanoue, Hidehiro Yamane, Keiko Ishikawa, Toshiro Sato, Masato Kubo, Shohei Hori, Tadatsugu Taniguchi, Masanori Hatakeyama, Koji Atarashi, Kenya Honda.
      Group 2 innate lymphoid cells (ILC2s) expressing IL-5 and IL-13 are localized at various mucosal tissues and play critical roles in the induction of type 2 inflammation, response to helminth infection, and tissue repair. Here, we reveal a unique ILC2 subset in the mouse intestine that constitutively expresses IL-4 together with GATA3, ST2, KLRG1, IL-17RB, and IL-5. In this subset, IL-4 expression is regulated by mechanisms similar to but distinct from those observed in T cells and is partly affected by IL-25 signaling. Although the absence of the microbiota had marginal effects, feeding mice with a vitamin B1-deficient diet compromised the number of intestinal IL-4+ ILC2s. The decrease in the number of IL-4+ ILC2s caused by the vitamin B1 deficiency was accompanied by a reduction in IL-25-producing tuft cells. Our findings reveal that dietary vitamin B1 plays a critical role in maintaining interaction between tuft cells and IL-4+ ILC2s, a previously uncharacterized immune cell population that may contribute to maintaining intestinal homeostasis.
    DOI:  https://doi.org/10.1084/jem.20221773
  26. Nat Commun. 2023 May 08. 14(1): 2642
    Cell-selective proteomics segregates pancreatic cancer subtypes by extracellular proteins in tumors and circulation.
    Jonathan J Swietlik, Stefanie Bärthel, Chiara Falcomatà, Diana Fink, Ankit Sinha, Jingyuan Cheng, Stefan Ebner, Peter Landgraf, Daniela C Dieterich, Henrik Daub, Dieter Saur, Felix Meissner.
      Cell-selective proteomics is a powerful emerging concept to study heterocellular processes in tissues. However, its high potential to identify non-cell-autonomous disease mechanisms and biomarkers has been hindered by low proteome coverage. Here, we address this limitation and devise a comprehensive azidonorleucine labeling, click chemistry enrichment, and mass spectrometry-based proteomics and secretomics strategy to dissect aberrant signals in pancreatic ductal adenocarcinoma (PDAC). Our in-depth co-culture and in vivo analyses cover more than 10,000 cancer cell-derived proteins and reveal systematic differences between molecular PDAC subtypes. Secreted proteins, such as chemokines and EMT-promoting matrisome proteins, associated with distinct macrophage polarization and tumor stromal composition, differentiate classical and mesenchymal PDAC. Intriguingly, more than 1,600 cancer cell-derived proteins including cytokines and pre-metastatic niche formation-associated factors in mouse serum reflect tumor activity in circulation. Our findings highlight how cell-selective proteomics can accelerate the discovery of diagnostic markers and therapeutic targets in cancer.
    DOI:  https://doi.org/10.1038/s41467-023-38171-8
  27. Commun Biol. 2023 May 09. 6(1): 500
    Anti-human-TIGIT agonistic antibody ameliorates autoimmune diseases by inhibiting Tfh and Tph cells and enhancing Treg cells.
    Marenori Kojima, Katsuya Suzuki, Masaru Takeshita, Masaki Ohyagi, Mana Iizuka, Humitsugu Yamane, Keiko Koga, Taku Kouro, Yoshiaki Kassai, Tomoki Yoshihara, Ryutaro Adachi, Kentarou Hashikami, Yuichiro Ota, Keiko Yoshimoto, Yuko Kaneko, Rimpei Morita, Akihiko Yoshimura, Tsutomu Takeuchi.
      T cells play important roles in autoimmune diseases, but it remains unclear how to optimally manipulate them. We focused on the T cell immunoreceptor with Ig and ITIM domains (TIGIT), a coinhibitory molecule that regulates and is expressed in T cells. In autoimmune diseases, the association between TIGIT-expressing cells and pathogenesis and the function of human-TIGIT (hu-TIGIT) signalling modification have not been fully elucidated. Here we generated anti-hu-TIGIT agonistic monoclonal antibodies (mAbs) and generated hu-TIGIT knock-in mice to accurately evaluate the efficacy of mAb function. Our mAb suppressed the activation of CD4+ T cells, especially follicular helper T and peripheral helper T cells that highly expressed TIGIT, and enhanced the suppressive function of naïve regulatory T cells. These results indicate that our mAb has advantages in restoring the imbalance of T cells that are activated in autoimmune diseases and suggest potential clinical applications for anti-hu-TIGIT agonistic mAbs as therapeutic agents.
    DOI:  https://doi.org/10.1038/s42003-023-04874-3
  28. Nat Med. 2023 May 09.
    Organ-specific aging and the risk of chronic diseases.
    Mahdi Moqri, Michael Snyder.
      
    DOI:  https://doi.org/10.1038/s41591-023-02338-z
  29. Nat Ecol Evol. 2023 May 08.
    PLIN2-induced ectopic lipid accumulation promotes muscle ageing in gregarious locusts.
    Siyuan Guo, Li Hou, Liushu Dong, Xin Nie, Le Kang, Xianhui Wang.
      Ageing plasticity represents the flexibility of the ageing process in response to non-genetic factors, occurring commonly in animals. However, the regulatory mechanisms underlying ageing plasticity are largely unclear. The density-dependent polyphenism of locusts, Locusta migratoria, displays dramatic lifespan divergence between solitary and gregarious phases, providing a useful system for studying ageing plasticity. Here, we found that gregarious locusts displayed faster locomotor deficits and increased muscle degeneration on ageing than solitary locusts. Comparative transcriptome analysis in flight muscles revealed significant differences in transcriptional patterns on ageing between two phases. RNA interference screening showed that the knockdown of the upregulated PLIN2 gene significantly relieved the ageing-related flight impairments in gregarious locusts. Mechanistically, the gradual upregulation of PLIN2 could induce the accumulation of ectopic lipid droplets and triacylglycerols in flight muscles during the ageing process. Further experiments suggested that ectopic lipid accumulation led to an ageing-related β-oxidation decline through limiting fatty acid transport and content. These findings reveal the key roles of lipid metabolism in the differences of muscle ageing between solitary and gregarious locusts and provide a potential mechanism underlying environment-induced muscle ageing plasticity.
    DOI:  https://doi.org/10.1038/s41559-023-02059-z
  30. Nat Rev Immunol. 2023 May 10.
    How nociceptors shape dendritic cell responses.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-023-00886-6
  31. Proc Natl Acad Sci U S A. 2023 05 16. 120(20): e2208673120
    Croquemort elicits activation of the immune deficiency pathway in ticks.
    Anya J O'Neal, Nisha Singh, Agustin Rolandelli, Hanna J Laukaitis, Xiaowei Wang, Dana K Shaw, Brianna D Young, Sukanya Narasimhan, Shraboni Dutta, Greg A Snyder, Sourabh Samaddar, Liron Marnin, L Rainer Butler, M Tays Mendes, Francy E Cabrera Paz, Luisa M Valencia, Eric J Sundberg, Erol Fikrig, Utpal Pal, David J Weber, Joao H F Pedra.
      The immune deficiency (IMD) pathway directs host defense in arthropods upon bacterial infection. In Pancrustacea, peptidoglycan recognition proteins sense microbial moieties and initiate nuclear factor-κB-driven immune responses. Proteins that elicit the IMD pathway in non-insect arthropods remain elusive. Here, we show that an Ixodes scapularis homolog of croquemort (Crq), a CD36-like protein, promotes activation of the tick IMD pathway. Crq exhibits plasma membrane localization and binds the lipid agonist 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol. Crq regulates the IMD and jun N-terminal kinase signaling cascades and limits the acquisition of the Lyme disease spirochete B. burgdorferi. Additionally, nymphs silenced for crq display impaired feeding and delayed molting to adulthood due to a deficiency in ecdysteroid synthesis. Collectively, we establish a distinct mechanism for arthropod immunity outside of insects and crustaceans.
    Keywords:  arthropod immunology; entomology; ticks
    DOI:  https://doi.org/10.1073/pnas.2208673120
  32. Immunity. 2023 Apr 25. pii: S1074-7613(23)00171-1. [Epub ahead of print]
    Phage display sequencing reveals that genetic, environmental, and intrinsic factors influence variation of human antibody epitope repertoire.
    Lifelines Cohort Study
      Phage-displayed immunoprecipitation sequencing (PhIP-seq) has enabled high-throughput profiling of human antibody repertoires. However, a comprehensive overview of environmental and genetic determinants shaping human adaptive immunity is lacking. In this study, we investigated the effects of genetic, environmental, and intrinsic factors on the variation in human antibody repertoires. We characterized serological antibody repertoires against 344,000 peptides using PhIP-seq libraries from a wide range of microbial and environmental antigens in 1,443 participants from a population cohort. We detected individual-specificity, temporal consistency, and co-housing similarities in antibody repertoires. Genetic analyses showed the involvement of the HLA, IGHV, and FUT2 gene regions in antibody-bound peptide reactivity. Furthermore, we uncovered associations between phenotypic factors (including age, cell counts, sex, smoking behavior, and allergies, among others) and particular antibody-bound peptides. Our results indicate that human antibody epitope repertoires are shaped by both genetics and environmental exposures and highlight specific signatures of distinct phenotypes and genotypes.
    Keywords:  PhIP-seq; antibody repertoire; environment; genetics; lifestyle
    DOI:  https://doi.org/10.1016/j.immuni.2023.04.003
  33. Nat Commun. 2023 May 09. 14(1): 2663
    Artificial Hsp104-mediated systems for re-localizing protein aggregates.
    Arthur Fischbach, Angela Johns, Kara L Schneider, Xinxin Hao, Peter Tessarz, Thomas Nyström.
      Spatial Protein Quality Control (sPQC) sequesters misfolded proteins into specific, organelle-associated inclusions within the cell to control their toxicity. To approach the role of sPQC in cellular fitness, neurodegenerative diseases and aging, we report on the construction of Hsp100-based systems in budding yeast cells, which can artificially target protein aggregates to non-canonical locations. We demonstrate that aggregates of mutant huntingtin (mHtt), the disease-causing agent of Huntington's disease can be artificially targeted to daughter cells as well as to eisosomes and endosomes with this approach. We find that the artificial removal of mHtt inclusions from mother cells protects them from cell death suggesting that even large mHtt inclusions may be cytotoxic, a trait that has been widely debated. In contrast, removing inclusions of endogenous age-associated misfolded proteins does not significantly affect the lifespan of mother cells. We demonstrate also that this approach is able to manipulate mHtt inclusion formation in human cells and has the potential to be useful as an alternative, complementary approach to study the role of sPQC, for example in aging and neurodegenerative disease.
    DOI:  https://doi.org/10.1038/s41467-023-37706-3
  34. Nat Commun. 2023 May 10. 14(1): 2686
    The PECAn image and statistical analysis pipeline identifies Minute cell competition genes and features.
    Michael E Baumgartner, Paul F Langton, Remi Logeay, Alex Mastrogiannopoulos, Anna Nilsson-Takeuchi, Iwo Kucinski, Jules Lavalou, Eugenia Piddini.
      Investigating organ biology often requires methodologies to induce genetically distinct clones within a living tissue. However, the 3D nature of clones makes sample image analysis challenging and slow, limiting the amount of information that can be extracted manually. Here we develop PECAn, a pipeline for image processing and statistical data analysis of complex multi-genotype 3D images. PECAn includes data handling, machine-learning-enabled segmentation, multivariant statistical analysis, and graph generation. This enables researchers to perform rigorous analyses rapidly and at scale, without requiring programming skills. We demonstrate the power of this pipeline by applying it to the study of Minute cell competition. We find an unappreciated sexual dimorphism in Minute cell growth in competing wing discs and identify, by statistical regression analysis, tissue parameters that model and correlate with competitive death. Furthermore, using PECAn, we identify several genes with a role in cell competition by conducting an RNAi-based screen.
    DOI:  https://doi.org/10.1038/s41467-023-38287-x
  35. Curr Opin Immunol. 2023 May 05. pii: S0952-7915(23)00051-1. [Epub ahead of print]83 102332
    'Persistent germinal center responses: slow-growing trees bear the best fruits'.
    Hanover C Matz, Katherine M McIntire, Ali H Ellebedy.
      Germinal centers (GCs) are key microanatomical sites in lymphoid organs where responding B cells mature and undergo affinity-based selection. The duration of the GC reaction has long been assumed to be relatively brief, but recent studies in humans, nonhuman primates, and mice indicate that GCs can last for weeks to months after initial antigen exposure. This review examines recent studies investigating the factors that influence GC duration, including antigen persistence, T-follicular helper cells, and mode of immunization. Potential mechanisms for how persistent GCs influence the B-cell repertoire are considered. Overall, these studies provide a blueprint for how to design better vaccines that elicit persistent GC responses.
    DOI:  https://doi.org/10.1016/j.coi.2023.102332
  36. Nat Genet. 2023 May;55(5): 796-806
    Genetic architecture of the inflammatory bowel diseases across East Asian and European ancestries.
    FinnGen
      Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract with the following two subtypes: Crohn's disease (CD) and ulcerative colitis (UC). To date, most IBD genetic associations were derived from individuals of European (EUR) ancestries. Here we report the largest IBD study of individuals of East Asian (EAS) ancestries, including 14,393 cases and 15,456 controls. We found 80 IBD loci in EAS alone and 320 when meta-analyzed with ~370,000 EUR individuals (~30,000 cases), among which 81 are new. EAS-enriched coding variants implicate many new IBD genes, including ADAP1 and GIT2. Although IBD genetic effects are generally consistent across ancestries, genetics underlying CD appears more ancestry dependent than UC, driven by allele frequency (NOD2) and effect (TNFSF15). We extended the IBD polygenic risk score (PRS) by incorporating both ancestries, greatly improving its accuracy and highlighting the importance of diversity for the equitable deployment of PRS.
    DOI:  https://doi.org/10.1038/s41588-023-01384-0
  37. Nat Commun. 2023 May 08. 14(1): 2651
    Hepatic stellate cell stearoyl co-A desaturase activates leukotriene B4 receptor 2 - β-catenin cascade to promote liver tumorigenesis.
    Sonal Sinha, Satoka Aizawa, Yasuhiro Nakano, Alexander Rialdi, Hye Yeon Choi, Rajan Shrestha, Stephanie Q Pan, Yibu Chen, Meng Li, Audrey Kapelanski-Lamoureux, Gregory Yochum, Linda Sher, Satdarshan Paul Monga, Anthoula Lazaris, Keigo Machida, Michael Karin, Ernesto Guccione, Hidekazu Tsukamoto.
      Hepatocellular carcinoma (HCC) is the 3rd most deadly malignancy. Activated hepatic stellate cells (aHSC) give rise to cancer-associated fibroblasts in HCC and are considered a potential therapeutic target. Here we report that selective ablation of stearoyl CoA desaturase-2 (Scd2) in aHSC globally suppresses nuclear CTNNB1 and YAP1 in tumors and tumor microenvironment and prevents liver tumorigenesis in male mice. Tumor suppression is associated with reduced leukotriene B4 receptor 2 (LTB4R2) and its high affinity oxylipin ligand, 12-hydroxyheptadecatrienoic acid (12-HHTrE). Genetic or pharmacological inhibition of LTB4R2 recapitulates CTNNB1 and YAP1 inactivation and tumor suppression in culture and in vivo. Single cell RNA sequencing identifies a subset of tumor-associated aHSC expressing Cyp1b1 but no other 12-HHTrE biosynthetic genes. aHSC release 12-HHTrE in a manner dependent on SCD and CYP1B1 and their conditioned medium reproduces the LTB4R2-mediated tumor-promoting effects of 12-HHTrE in HCC cells. CYP1B1-expressing aHSC are detected in proximity of LTB4R2-positive HCC cells and the growth of patient HCC organoids is blunted by LTB4R2 antagonism or knockdown. Collectively, our findings suggest aHSC-initiated 12-HHTrE-LTB4R2-CTNNB1-YAP1 pathway as a potential HCC therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-023-38406-8
  38. Nat Commun. 2023 May 11. 14(1): 2721
    Neonatal immune challenge poses a sex-specific risk for epigenetic microglial reprogramming and behavioral impairment.
    Marius Schwabenland, Omar Mossad, Annika Sievert, Adam G Peres, Elena Ringel, Sebastian Baasch, Julia Kolter, Giulia Cascone, Nikolaos Dokalis, Andreas Vlachos, Zsolt Ruzsics, Philipp Henneke, Marco Prinz, Thomas Blank.
      While the precise processes underlying a sex bias in the development of central nervous system (CNS) disorders are unknown, there is growing evidence that an early life immune activation can contribute to the disease pathogenesis. When we mimicked an early systemic viral infection or applied murine cytomegalovirus (MCMV) systemically in neonatal female and male mice, only male adolescent mice presented behavioral deficits, including reduced social behavior and cognition. This was paralleled by an increased amount of infiltrating T cells in the brain parenchyma, enhanced interferon-γ (IFNγ) signaling, and epigenetic reprogramming of microglial cells. These microglial cells showed increased phagocytic activity, which resulted in abnormal loss of excitatory synapses within the hippocampal brain region. None of these alterations were seen in female adolescent mice. Our findings underscore the early postnatal period's susceptibility to cause sex-dependent long-term CNS deficiencies following infections.
    DOI:  https://doi.org/10.1038/s41467-023-38373-0
  39. PLoS Pathog. 2023 May;19(5): e1011340
    Roles of long non-coding RNAs in plant immunity.
    Juan Huang, Wenling Zhou, Xiaoming Zhang, Yi Li.
      Robust plant immune systems are fine-tuned by both protein-coding genes and non-coding RNAs. Long non-coding RNAs (lncRNAs) refer to RNAs with a length of more than 200 nt and usually do not have protein-coding function and do not belong to any other well-known non-coding RNA types. The non-protein-coding, low expression, and non-conservative characteristics of lncRNAs restrict their recognition. Although studies of lncRNAs in plants are in the early stage, emerging studies have shown that plants employ lncRNAs to regulate plant immunity. Moreover, in response to stresses, numerous lncRNAs are differentially expressed, which manifests the actions of low-expressed lncRNAs and makes plant-microbe/insect interactions a convenient system to study the functions of lncRNAs. Here, we summarize the current advances in plant lncRNAs, discuss their regulatory effects in different stages of plant immunity, and highlight their roles in diverse plant-microbe/insect interactions. These insights will not only strengthen our understanding of the roles and actions of lncRNAs in plant-microbe/insect interactions but also provide novel insight into plant immune responses and a basis for further research in this field.
    DOI:  https://doi.org/10.1371/journal.ppat.1011340
  40. Nat Commun. 2023 May 08. 14(1): 2650
    Plasmodium falciparum has evolved multiple mechanisms to hijack human immunoglobulin M.
    Chenggong Ji, Hao Shen, Chen Su, Yaxin Li, Shihua Chen, Thomas H Sharp, Junyu Xiao.
      Plasmodium falciparum causes the most severe malaria in humans. Immunoglobulin M (IgM) serves as the first line of humoral defense against infection and potently activates the complement pathway to facilitate P. falciparum clearance. A number of P. falciparum proteins bind IgM, leading to immune evasion and severe disease. However, the underlying molecular mechanisms remain unknown. Here, using high-resolution cryo-electron microscopy, we delineate how P. falciparum proteins VAR2CSA, TM284VAR1, DBLMSP, and DBLMSP2 target IgM. Each protein binds IgM in a different manner, and together they present a variety of Duffy-binding-like domain-IgM interaction modes. We further show that these proteins interfere directly with IgM-mediated complement activation in vitro, with VAR2CSA exhibiting the most potent inhibitory effect. These results underscore the importance of IgM for human adaptation of P. falciparum and provide critical insights into its immune evasion mechanism.
    DOI:  https://doi.org/10.1038/s41467-023-38320-z
  41. Immunity. 2023 May 09. pii: S1074-7613(23)00175-9. [Epub ahead of print]56(5): 900-902
    Macrophages show up in style when Th2 lymphocytes organize their homecoming.
    Xin Li, Claudia V Jakubzick.
      Monocytes can differentiate into tissue-resident pleural macrophages, but the mechanisms underlying this process are not yet fully understood. In this issue of Immunity, Finlay et al.1 show that Th2 cytokines promote this differentiation in resistant mice infected with Litomosoides sigmodontis.
    DOI:  https://doi.org/10.1016/j.immuni.2023.04.007
  42. Nat Methods. 2023 May 08.
    Genome-wide profiling of prime editor off-target sites in vitro and in vivo using PE-tag.
    Shun-Qing Liang, Pengpeng Liu, Karthikeyan Ponnienselvan, Sneha Suresh, Zexiang Chen, Christian Kramme, Pranam Chatterjee, Lihua Julie Zhu, Erik J Sontheimer, Wen Xue, Scot A Wolfe.
      Prime editors have a broad range of potential research and clinical applications. However, methods to delineate their genome-wide editing activities have generally relied on indirect genome-wide editing assessments or the computational prediction of near-cognate sequences. Here we describe a genome-wide approach for the identification of potential prime editor off-target sites, which we call PE-tag. This method relies on the attachment or insertion of an amplification tag at sites of prime editor activity to allow their identification. PE-tag enables genome-wide profiling of off-target sites in vitro using extracted genomic DNA, in mammalian cell lines and in the adult mouse liver. PE-tag components can be delivered in a variety of formats for off-target site detection. Our studies are consistent with the high specificity previously described for prime editor systems, but we find that off-target editing rates are influenced by prime editing guide RNA design. PE-tag represents an accessible, rapid and sensitive approach for the genome-wide identification of prime editor activity and the evaluation of prime editor safety.
    DOI:  https://doi.org/10.1038/s41592-023-01859-2
  43. Nat Immunol. 2023 May 08.
    CD4+ T cell memory.
    Marco Künzli, David Masopust.
      Specialized subpopulations of CD4+ T cells survey major histocompatibility complex class II-peptide complexes to control phagosomal infections, help B cells, regulate tissue homeostasis and repair or perform immune regulation. Memory CD4+ T cells are positioned throughout the body and not only protect the tissues from reinfection and cancer, but also participate in allergy, autoimmunity, graft rejection and chronic inflammation. Here we provide updates on our understanding of the longevity, functional heterogeneity, differentiation, plasticity, migration and human immunodeficiency virus reservoirs as well as key technological advances that are facilitating the characterization of memory CD4+ T cell biology.
    DOI:  https://doi.org/10.1038/s41590-023-01510-4
  44. J Cell Biol. 2023 Aug 07. pii: e202211074. [Epub ahead of print]222(8):
    Centralspindlin proteins Pavarotti and Tumbleweed along with WASH regulate nuclear envelope budding.
    Kerri A Davidson, Mitsutoshi Nakamura, Jeffrey M Verboon, Susan M Parkhurst.
      Nuclear envelope (NE) budding is a nuclear pore-independent nuclear export pathway, analogous to the egress of herpesviruses, and required for protein quality control, synapse development, and mitochondrial integrity. The physical formation of NE buds is dependent on the Wiskott-Aldrich Syndrome protein, Wash, its regulatory complex (SHRC), and Arp2/3, and requires Wash's actin nucleation activity. However, the machinery governing cargo recruitment and organization within the NE bud remains unknown. Here, we identify Pavarotti (Pav) and Tumbleweed (Tum) as new molecular components of NE budding. Pav and Tum interact directly with Wash and define a second nuclear Wash-containing complex required for NE budding. Interestingly, we find that the actin-bundling activity of Pav is required, suggesting a structural role in the physical and/or organizational aspects of NE buds. Thus, Pav and Tum are providing exciting new entry points into the physical machineries of this alternative nuclear export pathway for large cargos during cell differentiation and development.
    DOI:  https://doi.org/10.1083/jcb.202211074
  45. Nature. 2023 May;617(7960): 242-243
    Human embryo science: can the world's regulators keep pace?
    Philip Ball.
      
    Keywords:  Developmental biology; Genetics; Policy
    DOI:  https://doi.org/10.1038/d41586-023-01550-8
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