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Transcriptional reg...
Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency
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Cichocki, F (author)
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- Schlums, H (author)
- Karolinska Institutet
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Li, HC (author)
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Stache, V (author)
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Holmes, T (author)
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Lenvik, TR (author)
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Chiang, SCC (author)
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Miller, JS (author)
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- Meeths, M (author)
- Karolinska Institutet
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Anderson, SK (author)
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- Bryceson, YT (author)
- Karolinska Institutet
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(creator_code:org_t)
- 2014-05-19
- 2014
- English.
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In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 211:6, s. 1079-1091
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http://jem.rupress.o...
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https://doi.org/10.1...
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Abstract
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- 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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- By the author/editor
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Cichocki, F
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Schlums, H
-
Li, HC
-
Stache, V
-
Holmes, T
-
Lenvik, TR
-
show more...
-
Chiang, SCC
-
Miller, JS
-
Meeths, M
-
Anderson, SK
-
Bryceson, YT
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show less...
- Articles in the publication
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The Journal of e ...
- By the university
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Karolinska Institutet