RESUMO
The role of the autoimmune regulator (Aire) in central immune tolerance and thymic self-representation was first described more than 20 years ago, but fascinating new insights into its biology continue to emerge, particularly in the era of advanced single-cell genomics. We briefly describe the role of human genetics in the discovery of Aire, as well as insights into its function gained from genotype-phenotype correlations and the spectrum of Aire-associated autoimmunity-including insights from patients with Aire mutations with broad and diverse implications for human health. We then highlight emerging trends in Aire biology, focusing on three topic areas. First, we discuss medullary thymic epithelial diversity and the role of Aire in thymic epithelial development. Second, we highlight recent developments regarding the molecular mechanisms of Aire and its binding partners. Finally, we describe the rapidly evolving biology of the identity and function of extrathymic Aire-expressing cells (eTACs), and a novel eTAC subset called Janus cells, as well as their potential roles in immune homeostasis.
Assuntos
Proteína AIRE , Autoimunidade , Fatores de Transcrição , Humanos , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Animais , Timo/imunologia , Timo/metabolismo , Mutação , Tolerância Imunológica , Células Epiteliais/metabolismo , Células Epiteliais/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismoRESUMO
Vertebrate immune systems suppress viral infection using both innate restriction factors and adaptive immunity. Viruses mutate to escape these defenses, driving hosts to counterevolve to regain fitness. This cycle recurs repeatedly, resulting in an evolutionary arms race whose outcome depends on the pace and likelihood of adaptation by host and viral genes. Although viruses evolve faster than their vertebrate hosts, their proteins are subject to numerous functional constraints that impact the probability of adaptation. These constraints are globally defined by evolutionary landscapes, which describe the fitness and adaptive potential of all possible mutations. We review deep mutational scanning experiments mapping the evolutionary landscapes of both host and viral proteins engaged in arms races. For restriction factors and some broadly neutralizing antibodies, landscapes favor the host, which may help to level the evolutionary playing field against rapidly evolving viruses. We discuss the biophysical underpinnings of these landscapes and their therapeutic implications.
Assuntos
Viroses , Vírus , Animais , Evolução Biológica , Humanos , Mutação , Proteínas Virais , Viroses/genética , Vírus/genéticaRESUMO
Mammalian mitochondrial DNA (mtDNA) is replicated and transcribed by phage-like DNA and RNA polymerases, and our understanding of these processes has progressed substantially over the last several decades. Molecular mechanisms have been elucidated by biochemistry and structural biology and essential in vivo roles established by cell biology and mouse genetics. Single molecules of mtDNA are packaged by mitochondrial transcription factor A into mitochondrial nucleoids, and their level of compaction influences the initiation of both replication and transcription. Mutations affecting the molecular machineries replicating and transcribing mtDNA are important causes of human mitochondrial disease, reflecting the critical role of the genome in oxidative phosphorylation system biogenesis. Mechanisms controlling mtDNA replication and transcription still need to be clarified, and future research in this area is likely to open novel therapeutic possibilities for treating mitochondrial dysfunction.
Assuntos
Replicação do DNA , DNA Mitocondrial , Transcrição Gênica , Humanos , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Animais , Mitocôndrias/metabolismo , Mitocôndrias/genética , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Mutação , Proteínas Mitocondriais/metabolismo , Proteínas Mitocondriais/genéticaRESUMO
Activating mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most common cause of monogenic Parkinson's disease. LRRK2 is a large multidomain protein kinase that phosphorylates a specific subset of the â¼65 human Rab GTPases, which are master regulators of the secretory and endocytic pathways. After phosphorylation by LRRK2, Rabs lose the capacity to bind cognate effector proteins and guanine nucleotide exchange factors. Moreover, the phosphorylated Rabs cannot interact with their cognate prenyl-binding retrieval proteins (also known as guanine nucleotide dissociation inhibitors) and, thus, they become trapped on membrane surfaces. Instead, they gain the capacity to bind phospho-Rab-specific effector proteins, such as RILPL1, with resulting pathological consequences. Rab proteins also act upstream of LRRK2 by controlling its activation and recruitment onto membranes. LRRK2 signaling is counteracted by the phosphoprotein phosphatase PPM1H, which selectively dephosphorylates phospho-Rab proteins. We present here our current understanding of the structure, biochemical properties, and cell biology of LRRK2 and its related paralog LRRK1 and discuss how this information guides the generation of LRRK2 inhibitors for the potential benefit of patients.
Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Proteínas rab de Ligação ao GTP , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/química , Fosforilação , Doença de Parkinson/metabolismo , Doença de Parkinson/genética , Doença de Parkinson/patologia , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/química , Animais , Transdução de Sinais , Mutação , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/química , Ligação Proteica , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas Fosfatases/genética , Fosfoproteínas Fosfatases/químicaRESUMO
We examined the rate and nature of mitochondrial DNA (mtDNA) mutations in humans using sequence data from 64,806 contemporary Icelanders from 2,548 matrilines. Based on 116,663 mother-child transmissions, 8,199 mutations were detected, providing robust rate estimates by nucleotide type, functional impact, position, and different alleles at the same position. We thoroughly document the true extent of hypermutability in mtDNA, mainly affecting the control region but also some coding-region variants. The results reveal the impact of negative selection on viable deleterious mutations, including rapidly mutating disease-associated 3243A>G and 1555A>G and pre-natal selection that most likely occurs during the development of oocytes. Finally, we show that the fate of new mutations is determined by a drastic germline bottleneck, amounting to an average of 3 mtDNA units effectively transmitted from mother to child.
Assuntos
DNA Mitocondrial , Linhagem , Humanos , DNA Mitocondrial/genética , Feminino , Islândia , Masculino , Mutação , Taxa de MutaçãoRESUMO
This perspective focuses on advances in genome technology over the last 25 years and their impact on germline variant discovery within the field of human genetics. The field has witnessed tremendous technological advances from microarrays to short-read sequencing and now long-read sequencing. Each technology has provided genome-wide access to different classes of human genetic variation. We are now on the verge of comprehensive variant detection of all forms of variation for the first time with a single assay. We predict that this transition will further transform our understanding of human health and biology and, more importantly, provide novel insights into the dynamic mutational processes shaping our genomes.
Assuntos
Variação Estrutural do Genoma , Genômica , Humanos , Genômica/métodos , Mutação em Linhagem Germinativa , Mutação , TecnologiaRESUMO
Many types of tumor cells alter metabolic pathways to meet their energy and biosynthetic demands for proliferation or stress adaptation. In this issue of Cell, Kong et al. find that the glycolytic metabolite methylglyoxal causes cancer-associated mutant single-base substitution features by inducing BRCA2 proteolysis, leading to functional haploinsufficiency of BRCA2.
Assuntos
Proteína BRCA2 , Glicólise , Haploinsuficiência , Humanos , Proteína BRCA2/metabolismo , Proteína BRCA2/genética , Aldeído Pirúvico/metabolismo , MutaçãoRESUMO
A number of species have recently recovered from near-extinction. Although these species have avoided the immediate extinction threat, their long-term viability remains precarious due to the potential genetic consequences of population declines, which are poorly understood on a timescale beyond a few generations. Woolly mammoths (Mammuthus primigenius) became isolated on Wrangel Island around 10,000 years ago and persisted for over 200 generations before becoming extinct around 4,000 years ago. To study the evolutionary processes leading up to the mammoths' extinction, we analyzed 21 Siberian woolly mammoth genomes. Our results show that the population recovered quickly from a severe bottleneck and remained demographically stable during the ensuing six millennia. We find that mildly deleterious mutations gradually accumulated, whereas highly deleterious mutations were purged, suggesting ongoing inbreeding depression that lasted for hundreds of generations. The time-lag between demographic and genetic recovery has wide-ranging implications for conservation management of recently bottlenecked populations.
Assuntos
Extinção Biológica , Genoma , Mamutes , Mutação , Animais , Mamutes/genética , Genoma/genética , Sibéria , Filogenia , Evolução Molecular , Fatores de TempoRESUMO
The story of p53 is illuminating. Despite widespread attention, the tumor-suppressive functions of wild-type p53 or the oncogenic activities of its cancer-associated mutants are still not fully understood, and our discoveries have not yet led to major therapeutic breakthroughs. There is still much to learn about this fascinating protein.
Assuntos
Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Neoplasias/genética , Neoplasias/tratamento farmacológico , MutaçãoRESUMO
Hepatitis B virus (HBV) is a small double-stranded DNA virus that chronically infects 296 million people. Over half of its compact genome encodes proteins in two overlapping reading frames, and during evolution, multiple selective pressures can act on shared nucleotides. This study combines an RNA-based HBV cell culture system with deep mutational scanning (DMS) to uncouple cis- and trans-acting sequence requirements in the HBV genome. The results support a leaky ribosome scanning model for polymerase translation, provide a fitness map of the HBV polymerase at single-nucleotide resolution, and identify conserved prolines adjacent to the HBV polymerase termination codon that stall ribosomes. Further experiments indicated that stalled ribosomes tether the nascent polymerase to its template RNA, ensuring cis-preferential RNA packaging and reverse transcription of the HBV genome.
Assuntos
Vírus da Hepatite B , Transcrição Reversa , Humanos , Genoma Viral/genética , Vírus da Hepatite B/genética , Mutação , Ribossomos/metabolismo , RNA Viral/genética , RNA Viral/metabolismo , Linhagem CelularRESUMO
Precise control of gene expression levels is essential for normal cell functions, yet how they are defined and tightly maintained, particularly at intermediate levels, remains elusive. Here, using a series of newly developed sequencing, imaging, and functional assays, we uncover a class of transcription factors with dual roles as activators and repressors, referred to as condensate-forming level-regulating dual-action transcription factors (TFs). They reduce high expression but increase low expression to achieve stable intermediate levels. Dual-action TFs directly exert activating and repressing functions via condensate-forming domains that compartmentalize core transcriptional unit selectively. Clinically relevant mutations in these domains, which are linked to a range of developmental disorders, impair condensate selectivity and dual-action TF activity. These results collectively address a fundamental question in expression regulation and demonstrate the potential of level-regulating dual-action TFs as powerful effectors for engineering controlled expression levels.
Assuntos
Fatores de Transcrição , Animais , Humanos , Camundongos , Regulação da Expressão Gênica , Mutação , Proteínas Repressoras/metabolismo , Proteínas Repressoras/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Linhagem CelularRESUMO
Discoveries of the roles of RAS oncogenes in cancer development four decades ago opened the door to proving that tumor development is driven by somatic mutations' altering the genomes of cancer cells. These discoveries led to illusions about the simplicity of cancer pathogenesis and how cancer could be cured.
Assuntos
Genes ras , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Oncogenes , MutaçãoRESUMO
The Crumbs homolog 1 (CRB1) gene is associated with retinal degeneration, most commonly Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP). Here, we demonstrate that murine retinas bearing the Rd8 mutation of Crb1 are characterized by the presence of intralesional bacteria. While normal CRB1 expression was enriched in the apical junctional complexes of retinal pigment epithelium and colonic enterocytes, Crb1 mutations dampened its expression at both sites. Consequent impairment of the outer blood retinal barrier and colonic intestinal epithelial barrier in Rd8 mice led to the translocation of intestinal bacteria from the lower gastrointestinal (GI) tract to the retina, resulting in secondary retinal degeneration. Either the depletion of bacteria systemically or the reintroduction of normal Crb1 expression colonically rescued Rd8-mutation-associated retinal degeneration without reversing the retinal barrier breach. Our data elucidate the pathogenesis of Crb1-mutation-associated retinal degenerations and suggest that antimicrobial agents have the potential to treat this devastating blinding disease.
Assuntos
Proteínas do Tecido Nervoso , Degeneração Retiniana , Animais , Camundongos , Translocação Bacteriana , Proteínas do Olho/genética , Amaurose Congênita de Leber/genética , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Retina/metabolismo , Degeneração Retiniana/genética , Retinose Pigmentar/genética , Retinose Pigmentar/metabolismo , Retinose Pigmentar/patologiaRESUMO
A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. In people living with HIV-1, bnAbs take years to develop. The HVTN 133 clinical trial studied a peptide/liposome immunogen targeting B cell lineages of HIV-1 envelope (Env) membrane-proximal external region (MPER) bnAbs (NCT03934541). Here, we report MPER peptide-liposome induction of polyclonal HIV-1 B cell lineages of mature bnAbs and their precursors, the most potent of which neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains with lineage initiation after the second immunization. Neutralization was enhanced by vaccine selection of improbable mutations that increased antibody binding to gp41 and lipids. This study demonstrates proof of concept for rapid vaccine induction of human B cell lineages with heterologous neutralizing activity and selection of antibody improbable mutations and outlines a path for successful HIV-1 vaccine development.
Assuntos
Vacinas contra a AIDS , Anticorpos Neutralizantes , Linfócitos B , Anticorpos Anti-HIV , HIV-1 , Humanos , Vacinas contra a AIDS/imunologia , HIV-1/imunologia , Anticorpos Neutralizantes/imunologia , Linfócitos B/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Linhagem da Célula , Lipossomos , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Mutação , Proteína gp41 do Envelope de HIV/imunologiaRESUMO
The development of perennial crops holds great promise for sustainable agriculture and food security. However, the evolution of the transition between perenniality and annuality is poorly understood. Here, using two Brassicaceae species, Crucihimalaya himalaica and Erysimum nevadense, as polycarpic perennial models, we reveal that the transition from polycarpic perennial to biennial and annual flowering behavior is a continuum determined by the dosage of three closely related MADS-box genes. Diversification of the expression patterns, functional strengths, and combinations of these genes endows species with the potential to adopt various life-history strategies. Remarkably, we find that a single gene among these three is sufficient to convert winter-annual or annual Brassicaceae plants into polycarpic perennial flowering plants. Our work delineates a genetic basis for the evolution of diverse life-history strategies in plants and lays the groundwork for the generation of diverse perennial Brassicaceae crops in the future.
Assuntos
Brassicaceae , Flores , Regulação da Expressão Gênica de Plantas , Brassicaceae/genética , Brassicaceae/fisiologia , Produtos Agrícolas/genética , Flores/genética , Flores/fisiologia , Proteínas de Domínio MADS/genética , Proteínas de Domínio MADS/metabolismo , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Genoma de Planta , Fenômenos Fisiológicos Vegetais , Mapeamento Cromossômico , MutaçãoRESUMO
Characterizing somatic mutations in the brain is important for disentangling the complex mechanisms of aging, yet little is known about mutational patterns in different brain cell types. Here, we performed whole-genome sequencing (WGS) of 86 single oligodendrocytes, 20 mixed glia, and 56 single neurons from neurotypical individuals spanning 0.4-104 years of age and identified >92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels). Although both cell types accumulate somatic mutations linearly with age, oligodendrocytes accumulated sSNVs 81% faster than neurons and indels 28% slower than neurons. Correlation of mutations with single-nucleus RNA profiles and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These stark differences suggest an assortment of active mutagenic processes in oligodendrocytes and neurons.
Assuntos
Envelhecimento , Encéfalo , Neurônios , Oligodendroglia , Humanos , Envelhecimento/genética , Envelhecimento/patologia , Cromatina/genética , Cromatina/metabolismo , Mutação , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Análise da Expressão Gênica de Célula Única , Sequenciamento Completo do Genoma , Encéfalo/metabolismo , Encéfalo/patologia , Polimorfismo de Nucleotídeo Único , Mutação INDEL , Bancos de Espécimes Biológicos , Células Precursoras de Oligodendrócitos/metabolismo , Células Precursoras de Oligodendrócitos/patologiaRESUMO
Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.
Assuntos
Proteína BRCA2 , Neoplasias da Mama , Glicólise , Aldeído Pirúvico , Animais , Proteína BRCA2/metabolismo , Proteína BRCA2/genética , Camundongos , Humanos , Feminino , Aldeído Pirúvico/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Haploinsuficiência , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Mutação , Dano ao DNA , Reparo do DNA , Linhagem Celular TumoralRESUMO
Clonal hematopoiesis of indeterminate potential (CHIP) arises from aging-associated acquired mutations in hematopoietic progenitors, which display clonal expansion and produce phenotypically altered leukocytes. We associated CHIP-DNMT3A mutations with a higher prevalence of periodontitis and gingival inflammation among 4,946 community-dwelling adults. To model DNMT3A-driven CHIP, we used mice with the heterozygous loss-of-function mutation R878H, equivalent to the human hotspot mutation R882H. Partial transplantation with Dnmt3aR878H/+ bone marrow (BM) cells resulted in clonal expansion of mutant cells into both myeloid and lymphoid lineages and an elevated abundance of osteoclast precursors in the BM and osteoclastogenic macrophages in the periphery. DNMT3A-driven clonal hematopoiesis in recipient mice promoted naturally occurring periodontitis and aggravated experimentally induced periodontitis and arthritis, associated with enhanced osteoclastogenesis, IL-17-dependent inflammation and neutrophil responses, and impaired regulatory T cell immunosuppressive activity. DNMT3A-driven clonal hematopoiesis and, subsequently, periodontitis were suppressed by rapamycin treatment. DNMT3A-driven CHIP represents a treatable state of maladaptive hematopoiesis promoting inflammatory bone loss.
Assuntos
Hematopoiese Clonal , DNA (Citosina-5-)-Metiltransferases , DNA Metiltransferase 3A , Periodontite , Animais , DNA (Citosina-5-)-Metiltransferases/metabolismo , DNA (Citosina-5-)-Metiltransferases/genética , Camundongos , Hematopoiese Clonal/genética , Humanos , Periodontite/genética , Periodontite/patologia , Mutação , Masculino , Feminino , Inflamação/genética , Inflamação/patologia , Osteoclastos/metabolismo , Camundongos Endogâmicos C57BL , Adulto , Interleucina-17/metabolismo , Interleucina-17/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Hematopoese/genética , Osteogênese/genética , Células-Tronco Hematopoéticas/metabolismo , Reabsorção Óssea/genética , Reabsorção Óssea/patologia , Pessoa de Meia-IdadeRESUMO
Clinical trials have identified ARID1A mutations as enriched among patients who respond favorably to immune checkpoint blockade (ICB) in several solid tumor types independent of microsatellite instability. We show that ARID1A loss in murine models is sufficient to induce anti-tumor immune phenotypes observed in ARID1A mutant human cancers, including increased CD8+ T cell infiltration and cytolytic activity. ARID1A-deficient cancers upregulated an interferon (IFN) gene expression signature, the ARID1A-IFN signature, associated with increased R-loops and cytosolic single-stranded DNA (ssDNA). Overexpression of the R-loop resolving enzyme, RNASEH2B, or cytosolic DNase, TREX1, in ARID1A-deficient cells prevented cytosolic ssDNA accumulation and ARID1A-IFN gene upregulation. Further, the ARID1A-IFN signature and anti-tumor immunity were driven by STING-dependent type I IFN signaling, which was required for improved responsiveness of ARID1A mutant tumors to ICB treatment. These findings define a molecular mechanism underlying anti-tumor immunity in ARID1A mutant cancers.
Assuntos
Linfócitos T CD8-Positivos , Proteínas de Ligação a DNA , Interferon Tipo I , Proteínas de Membrana , Neoplasias , Transdução de Sinais , Fatores de Transcrição , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Exodesoxirribonucleases/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Mutação , Neoplasias/imunologia , Neoplasias/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Fatores de Transcrição/metabolismo , Masculino , Quimiocinas/genética , Quimiocinas/metabolismoRESUMO
Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.