ArticleThe Journal of experimental medicine2014
Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency.
Article in The Journal of experimental medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 42 citations in OpenAlex.
- Adults with septic shock and extreme hyperferritinemia exhibit pathogenic immune variation.Genes and immunity · 2019Trial
- Genetic and clinical characteristics of 54 pediatric lymphoma patients with variant mutation sites ofHaematologica · 2026Article
- Lytic IFNγ is stored in cytotoxic granules and coreleased with granzyme B to mediate cytotoxic T lymphocyte killing.Cellular & molecular immunology · 2026Article
- Single-cell analysis of UNC13D-mediated immune and dedifferentiation heterogeneity in acute myeloid leukemia and development of a prognostic model.Translational cancer research · 2026Article
- Histone methylation in Epstein-Barr virus-associated diseases.Epigenomics · 2024Review
- Functional role of UNC13D in immune diseases and its therapeutic applications.Frontiers in immunology · 2024Review
- Laboratory Features and Pathology of Cytokine Storm Syndromes.Advances in experimental medicine and biology · 2024Review
- CD8Advances in experimental medicine and biology · 2024Review
- Genetics of Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis.Advances in experimental medicine and biology · 2024Review
- The Multifaceted Immunology of Cytokine Storm Syndrome.Journal of immunology (Baltimore, Md. : 1950) · 2023Review
- Article
- T Cell Defects: New Insights Into the Primary Resistance Factor to CD19/CD22 Cocktail CAR T-Cell Immunotherapy in Diffuse Large B-Cell Lymphoma.Frontiers in immunology · 2022Article
- Molecular regulation of the plasma membrane-proximal cellular steps involved in NK cell cytolytic function.Journal of cell science · 2020Review
- AlternativeFrontiers in immunology · 2020Article
- The Immunology of Macrophage Activation Syndrome.Frontiers in immunology · 2019Review
- Brief Report: Novel UNC13D Intronic Variant Disrupting an NF-κB Enhancer in a Patient With Recurrent Macrophage Activation Syndrome and Systemic Juvenile Idiopathic Arthritis.Arthritis & rheumatology (Hoboken, N.J.) · 2018Article
- Identification of an elaborate NK-specific system regulating HLA-C expression.PLoS genetics · 2018Article
- A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis.Journal of immunology (Baltimore, Md. : 1950) · 2016Article
- Diacylglycerol Kinases in T Cell Tolerance and Effector Function.Frontiers in cell and developmental biology · 2016Review
- Genetic predisposition to hemophagocytic lymphohistiocytosis: Report on 500 patients from the Italian registry.The Journal of allergy and clinical immunology · 2016Article
Corrections and comments
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Authors and funding
11 authors at 6 institutions in 4 countries.
Funding
Abstract
Autosomal recessive mutations in UNC13D, the gene that encodes Munc13-4, are associated with familial hemophagocytic lymphohistiocytosis type 3 (FHL3). Munc13-4 expression is obligatory for exocytosis of lytic granules, facilitating cytotoxicity by T cells and natural killer (NK) cells. The mechanisms regulating Munc13-4 expression are unknown. Here, we report that Munc13-4 is highly expressed in differentiated human NK cells and effector CD8(+) T lymphocytes. A UNC13D c.118-308C>T mutation, causative of FHL3, disrupted binding of the ETS family member ELF1 to a conserved intronic sequence. This mutation impairs UNC13D intron 1 recruitment of STAT4 and the chromatin remodeling complex component BRG1, diminishing active histone modifications at the locus. The intronic sequence acted as an overall enhancer of Munc13-4 expression in cytotoxic lymphocytes in addition to representing an alternative promoter encoding a novel Munc13-4 isoform. Mechanistically, T cell receptor engagement facilitated STAT4-dependent Munc13-4 expression in naive CD8(+) T lymphocytes. Collectively, our data demonstrates how chromatin remodeling within an evolutionarily conserved regulatory element in intron 1 of UNC13D regulates the induction of Munc13-4 expression in cytotoxic lymphocytes and suggests that an alternative Munc13-4 isoform is required for lymphocyte cytotoxicity. Thus, mutations associated with primary immunodeficiencies may cause disease by disrupting transcription factor binding.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.