bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–12–31
twelve papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Structural basis for DNA proofreading.
  2. Extracellular carriers control lipid-dependent secretion, delivery, and activity of WNT morphogens.
  3. Variants at the Interleukin 1 Gene Locus and Pericarditis.
  4. Multi-ancestry genome-wide association meta-analysis of Parkinson's disease.
  5. hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50.
  6. Macrophage-derived TNF-enriched tumour microenvironment shapes pancreatic ductal adenocarcinoma into the basal-like molecular phenotype through upregulating TAp63.
  7. ANGPTL4 binds to the leptin receptor to regulate ectopic bone formation.
  8. Human behavior and disease dynamics.
  9. Advancing precision medicine in type 2 diabetes.
  10. A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.
  11. IFN-β Pretreatment Alleviates Allogeneic Renal Tubular Epithelial Cell-Induced NK Cell Responses via the IRF7/HLA-E/NKG2A Axis.
  12. B cell phylogenetics in the single cell era.
  1. Nat Commun. 2023 Dec 27. 14(1): 8501
    Structural basis for DNA proofreading.
    Gina Buchel, Ashok R Nayak, Karl Herbine, Azadeh Sarfallah, Viktoriia O Sokolova, Angelica Zamudio-Ochoa, Dmitry Temiakov.
      DNA polymerase (DNAP) can correct errors in DNA during replication by proofreading, a process critical for cell viability. However, the mechanism by which an erroneously incorporated base translocates from the polymerase to the exonuclease site and the corrected DNA terminus returns has remained elusive. Here, we present an ensemble of nine high-resolution structures representing human mitochondrial DNA polymerase Gamma, Polγ, captured during consecutive proofreading steps. The structures reveal key events, including mismatched base recognition, its dissociation from the polymerase site, forward translocation of DNAP, alterations in DNA trajectory, repositioning and refolding of elements for primer separation, DNAP backtracking, and displacement of the mismatched base into the exonuclease site. Altogether, our findings suggest a conserved 'bolt-action' mechanism of proofreading based on iterative cycles of DNAP translocation without dissociation from the DNA, facilitating primer transfer between catalytic sites. Functional assays and mutagenesis corroborate this mechanism, connecting pathogenic mutations to crucial structural elements in proofreading steps.
    DOI:  https://doi.org/10.1038/s41467-023-44198-8
  2. Dev Cell. 2023 Dec 21. pii: S1534-5807(23)00648-2. [Epub ahead of print]
    Extracellular carriers control lipid-dependent secretion, delivery, and activity of WNT morphogens.
    Taciani de Almeida Magalhaes, Jingjing Liu, Charlene Chan, Kleiton Silva Borges, Jiuchun Zhang, Andrew J Kane, Bradley M Wierbowski, Yunhui Ge, Zhiwen Liu, Prabhath Mannam, Daniel Zeve, Ron Weiss, David T Breault, Pengxiang Huang, Adrian Salic.
      WNT morphogens trigger signaling pathways fundamental for embryogenesis, regeneration, and cancer. WNTs are modified with palmitoleate, which is critical for binding Frizzled (FZD) receptors and activating signaling. However, it is unknown how WNTs are released and spread from cells, given their strong lipid-dependent membrane attachment. We demonstrate that secreted FZD-related proteins and WNT inhibitory factor 1 are WNT carriers, potently releasing lipidated WNTs and forming active soluble complexes. WNT release occurs by direct handoff from the membrane protein WNTLESS to the carriers. In turn, carriers donate WNTs to glypicans and FZDs involved in WNT reception and to the NOTUM hydrolase, which antagonizes WNTs by lipid moiety removal. WNT transfer from carriers to FZDs is greatly facilitated by glypicans that serve as essential co-receptors in Wnt signaling. Thus, an extracellular network of carriers dynamically controls secretion, posttranslational regulation, and delivery of WNT morphogens, with important practical implications for regenerative medicine.
    Keywords:  WNT; extracellular; lipids; morphogen; receptor; signaling
    DOI:  https://doi.org/10.1016/j.devcel.2023.11.027
  3. JAMA Cardiol. 2023 Dec 27.
    Variants at the Interleukin 1 Gene Locus and Pericarditis.
    Danish Blood Donor Study Genomic Consortium
       Importance: Recurrent pericarditis is a treatment challenge and often a debilitating condition. Drugs inhibiting interleukin 1 cytokines are a promising new treatment option, but their use is based on scarce biological evidence and clinical trials of modest sizes, and the contributions of innate and adaptive immune processes to the pathophysiology are incompletely understood.
    Objective: To use human genomics, transcriptomics, and proteomics to shed light on the pathogenesis of pericarditis.
    Design, Setting, and Participants: This was a meta-analysis of genome-wide association studies of pericarditis from 5 countries. Associations were examined between the pericarditis-associated variants and pericarditis subtypes (including recurrent pericarditis) and secondary phenotypes. To explore mechanisms, associations with messenger RNA expression (cis-eQTL), plasma protein levels (pQTL), and CpG methylation of DNA (ASM-QTL) were assessed. Data from Iceland (deCODE genetics, 1983-2020), Denmark (Copenhagen Hospital Biobank/Danish Blood Donor Study, 1977-2022), the UK (UK Biobank, 1953-2021), the US (Intermountain, 1996-2022), and Finland (FinnGen, 1970-2022) were included. Data were analyzed from September 2022 to August 2023.
    Exposure: Genotype.
    Main Outcomes and Measures: Pericarditis.
    Results: In this genome-wide association study of 4894 individuals with pericarditis (mean [SD] age at diagnosis, 51.4 [17.9] years, 2734 [67.6%] male, excluding the FinnGen cohort), associations were identified with 2 independent common intergenic variants at the interleukin 1 locus on chromosome 2q14. The lead variant was rs12992780 (T) (effect allele frequency [EAF], 31%-40%; odds ratio [OR], 0.83; 95% CI, 0.79-0.87; P = 6.67 × 10-16), downstream of IL1B and the secondary variant rs7575402 (A or T) (EAF, 45%-55%; adjusted OR, 0.89; 95% CI, 0.85-0.93; adjusted P = 9.6 × 10-8). The lead variant rs12992780 had a smaller odds ratio for recurrent pericarditis (0.76) than the acute form (0.86) (P for heterogeneity = .03) and rs7575402 was associated with CpG methylation overlapping binding sites of 4 transcription factors known to regulate interleukin 1 production: PU.1 (encoded by SPI1), STAT1, STAT3, and CCAAT/enhancer-binding protein β (encoded by CEBPB).
    Conclusions and Relevance: This study found an association between pericarditis and 2 independent sequence variants at the interleukin 1 gene locus. This finding has the potential to contribute to development of more targeted and personalized therapy of pericarditis with interleukin 1-blocking drugs.
    DOI:  https://doi.org/10.1001/jamacardio.2023.4820
  4. Nat Genet. 2023 Dec 28.
    Multi-ancestry genome-wide association meta-analysis of Parkinson's disease.
    23andMe Research Team
      Although over 90 independent risk variants have been identified for Parkinson's disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson's disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations.
    DOI:  https://doi.org/10.1038/s41588-023-01584-8
  5. Mol Cell. 2023 Dec 20. pii: S1097-2765(23)00980-2. [Epub ahead of print]
    hRpn13 shapes the proteome and transcriptome through epigenetic factors HDAC8, PADI4, and transcription factor NF-κB p50.
    Vasty Osei-Amponsa, Monika Chandravanshi, Xiuxiu Lu, Valentin Magidson, Sudipto Das, Thorkell Andresson, Marzena Dyba, Venkata R Sabbasani, Rolf E Swenson, Caroline Fromont, Biraj Shrestha, Yongmei Zhao, Michelle E Clapp, Raj Chari, Kylie J Walters.
      The anti-cancer target hRpn13 is a proteasome substrate receptor. However, hRpn13-targeting molecules do not impair its interaction with proteasomes or ubiquitin, suggesting other critical cellular activities. We find that hRpn13 depletion causes correlated proteomic and transcriptomic changes, with pronounced effects in myeloma cells for cytoskeletal and immune response proteins and bone-marrow-specific arginine deiminase PADI4. Moreover, a PROTAC against hRpn13 co-depletes PADI4, histone deacetylase HDAC8, and DNA methyltransferase MGMT. PADI4 binds and citrullinates hRpn13 and proteasomes, and proteasomes from PADI4-inhibited myeloma cells exhibit reduced peptidase activity. When off proteasomes, hRpn13 can bind HDAC8, and this interaction inhibits HDAC8 activity. Further linking hRpn13 to transcription, its loss reduces nuclear factor κB (NF-κB) transcription factor p50, which proteasomes generate by cleaving its precursor protein. NF-κB inhibition depletes hRpn13 interactors PADI4 and HDAC8. Altogether, we find that hRpn13 acts dually in protein degradation and expression and that proteasome constituency and, in turn, regulation varies by cell type.
    Keywords:  HDAC8; MGMT; MYH10; NF-κB; PADI4; citrulline; cytoskeleton; gene regulation; hRpn13; proteasome
    DOI:  https://doi.org/10.1016/j.molcel.2023.11.035
  6. Clin Transl Med. 2023 Dec;13(12): e1520
    Macrophage-derived TNF-enriched tumour microenvironment shapes pancreatic ductal adenocarcinoma into the basal-like molecular phenotype through upregulating TAp63.
    Su Bin Lim, Jae-Il Choi, Yunjin Go, Yu-Jin Ha, Min Jae Yang, So-Hyun Park, Seokhwi Kim, You-Sun Kim, Dakeun Lee.
      
    DOI:  https://doi.org/10.1002/ctm2.1520
  7. Proc Natl Acad Sci U S A. 2024 Jan 02. 121(1): e2310685120
    ANGPTL4 binds to the leptin receptor to regulate ectopic bone formation.
    Hongling Hu, Sheng Luo, Pinglin Lai, Mingqiang Lai, Linlin Mao, Sheng Zhang, Yuanjun Jiang, Jiaxin Wen, Wu Zhou, Xiaolin Liu, Liang Wang, Minjun Huang, Yanjun Hu, Xiaoyang Zhao, Laixin Xia, Weijie Zhou, Yu Jiang, Zhipeng Zou, Anling Liu, Bin Guo, Xiaochun Bai.
      Leptin protein was thought to be unique to leptin receptor (LepR), but the phenotypes of mice with mutation in LepR [db/db (diabetes)] and leptin [ob/ob (obese)] are not identical, and the cause remains unclear. Here, we show that db/db, but not ob/ob, mice had defect in tenotomy-induced heterotopic ossification (HO), implicating alternative ligand(s) for LepR might be involved. Ligand screening revealed that ANGPTL4 (angiopoietin-like protein 4), a stress and fasting-induced factor, was elicited from brown adipose tissue after tenotomy, bound to LepR on PRRX1+ mesenchymal cells at the HO site, thus promotes chondrogenesis and HO development. Disruption of LepR in PRRX1+ cells, or lineage ablation of LepR+ cells, or deletion of ANGPTL4 impeded chondrogenesis and HO in mice. Together, these findings identify ANGPTL4 as a ligand for LepR to regulate the formation of acquired HO.
    Keywords:  ANGPTL4; heterotopic ossification; leptin receptor
    DOI:  https://doi.org/10.1073/pnas.2310685120
  8. Proc Natl Acad Sci U S A. 2024 Jan 02. 121(1): e2317211120
    Human behavior and disease dynamics.
    Carl T Bergstrom, William P Hanage.
      
    DOI:  https://doi.org/10.1073/pnas.2317211120
  9. Lancet Diabetes Endocrinol. 2023 Dec 21. pii: S2213-8587(23)00384-4. [Epub ahead of print]
    Advancing precision medicine in type 2 diabetes.
    Jose C Florez.
      
    DOI:  https://doi.org/10.1016/S2213-8587(23)00384-4
  10. Mol Cell. 2023 Dec 21. pii: S1097-2765(23)01014-6. [Epub ahead of print]
    A mitophagy sensor PPTC7 controls BNIP3 and NIX degradation to regulate mitochondrial mass.
    Yuqiu Sun, Yu Cao, Huayun Wan, Adalet Memetimin, Yang Cao, Lin Li, Chongyang Wu, Meng Wang, She Chen, Qi Li, Yan Ma, Mengqiu Dong, Hui Jiang.
      Mitophagy mediated by BNIP3 and NIX critically regulates mitochondrial mass. Cellular BNIP3 and NIX levels are tightly controlled by SCFFBXL4-mediated ubiquitination to prevent excessive mitochondrial loss and lethal disease. Here, we report that knockout of PPTC7, a mitochondrial matrix protein, hyperactivates BNIP3-/NIX-mediated mitophagy and causes perinatal lethality that is rescued by NIX knockout in mice. Biochemically, the PPTC7 precursor is trapped by BNIP3 and NIX to the mitochondrial outer membrane, where PPTC7 scaffolds assembly of a substrate-PPTC7-SCFFBXL4 holocomplex to degrade BNIP3 and NIX, forming a homeostatic regulatory loop. PPTC7 possesses an unusually weak mitochondrial targeting sequence to facilitate its outer membrane retention and mitophagy control. Starvation upregulates PPPTC7 expression in mouse liver to repress mitophagy, which critically maintains hepatic mitochondrial mass, bioenergetics, and gluconeogenesis. Collectively, PPTC7 functions as a mitophagy sensor that integrates homeostatic and physiological signals to dynamically control BNIP3 and NIX degradation, thereby maintaining mitochondrial mass and cellular homeostasis.
    Keywords:  Cullin; FBXL4; PPTC7; metabolism; mitochondrial mass; mitophagy receptors BNIP3 and NIX; ubiquitin
    DOI:  https://doi.org/10.1016/j.molcel.2023.11.038
  11. J Immunol. 2023 Dec 27. pii: ji2200941. [Epub ahead of print]
    IFN-β Pretreatment Alleviates Allogeneic Renal Tubular Epithelial Cell-Induced NK Cell Responses via the IRF7/HLA-E/NKG2A Axis.
    Xing Zhang, Junni Wang, Mowang Wang, Mengbao Du, Jianghua Chen, Limengmeng Wang, Jianyong Wu.
      Immune checkpoint molecules are promising targets for suppressing the immune response but have received little attention in immune tolerance induction in organ transplantation. In this study, we found that IFN-β could induce the expression of HLA-E as well as PD-L1 on human renal tubular epithelial cell line HK-2 and renal tissue of the C57BL/6 mouse. The JAK/STAT2 pathway was necessary for this process. Upregulation of both HLA-E and PD-L1 was fully abrogated by the JAK1/2 inhibitor ruxolitinib. Signaling pathway molecules, including STAT1, STAT2, mTOR, Tyk2, and p38 MAPK, were involved in HLA-E and PD-L1 upregulation. IRF7 is the key transcription factor responsible for the activation of HLA-E and PD-L1 promoters. Through screening an epigenetic regulation library, we found a natural compound, bisdemethoxycurcumin, enhanced IFN-β-induced HLA-E and PD-L1 expression in vitro and in vivo. In PBMC-derived CD56+ NK cells, we found that NKG2A but not PD1 was constitutively expressed, indicating HLA-E/NKG2A as a more potent target to induce tolerance to innate immune cells. Pretreating HK-2 cells by IFN-β significantly attenuated the degranulation of their coincubated NK cells and protected cells from NK-mediated lysis. In conclusion, IFN-β pretreatment could activate HLA-E and PD-L1 transcription through the JAK/STAT/IRF7 pathway and then could protect renal tubular epithelial cells from allogeneic immune attack mediated by NK cells.
    DOI:  https://doi.org/10.4049/jimmunol.2200941
  12. Trends Immunol. 2023 Dec 27. pii: S1471-4906(23)00258-2. [Epub ahead of print]
    B cell phylogenetics in the single cell era.
    Kenneth B Hoehn, Steven H Kleinstein.
      The widespread availability of single-cell RNA sequencing (scRNA-seq) has led to the development of new methods for understanding immune responses. Single-cell transcriptome data can now be paired with B cell receptor (BCR) sequences. However, RNA from BCRs cannot be analyzed like most other genes because BCRs are genetically diverse within individuals. In humans, BCRs are shaped through recombination followed by mutation and selection for antigen binding. As these processes co-occur with cell division, B cells can be studied using phylogenetic trees representing the mutations within a clone. B cell trees can link experimental timepoints, tissues, or cellular subtypes. Here, we review the current state and potential of how B cell phylogenetics can be combined with single-cell data to understand immune responses.
    Keywords:  B cell; B cell receptor; adaptive immunity; evolution; phylogenetics; single cell
    DOI:  https://doi.org/10.1016/j.it.2023.11.004
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