Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency.
Bottom Line: The mechanisms regulating Munc13-4 expression are unknown.This mutation impairs UNC13D intron 1 recruitment of STAT4 and the chromatin remodeling complex component BRG1, diminishing active histone modifications at the locus.Thus, mutations associated with primary immunodeficiencies may cause disease by disrupting transcription factor binding.
Affiliation: Centre for Infectious Medicine, Department of Medicine; Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden Division of Hematology, Oncology and Transplantation, University of Minnesota Cancer Center, Minneapolis, MN 55455.Show MeSH
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Mentions: Understanding how Munc13-4 expression is controlled in distinct lymphocyte subsets is of interest considering the pivotal role of this protein for lymphocyte cytotoxicity (Feldmann et al., 2003). A ubiquitous Munc13-4 expression pattern was initially reported by Koch and colleagues (Koch et al., 2000), but a more detailed analysis has not since been performed. To compare Munc13-4 expression levels between cytotoxic and noncytotoxic lymphocytes, we isolated lymphocyte subsets from the peripheral blood of healthy donors and performed Western blots for Munc13-4. Relative to CD19+ B cells, CD3−CD56+ NK cells expressed very high levels of Munc13-4. Moreover, CD4+ T cells expressed low levels of Munc13-4, whereas total CD8+ T cells expressed intermediate levels. To determine whether Munc13-4 is concomitantly induced along with the acquisition of lytic granules, we compared expression in CD56bright and CD56dim NK cells as well as in naive and effector CD8+ T cells. In both NK cells and CD8+ T cells, maturation and acquisition of lytic granules was associated with a marked increase in Munc13-4 expression, indicating that Munc13-4 is up-regulated during differentiation of cytotoxic lymphocyte subsets (Fig. 1, a and b). High levels of Munc13-4 expression thus correlate with a strong propensity to degranulate in response to engagement of activating receptors on cytotoxic T cells or NK cells (Chiang, et al., 2013). Notably, expression levels of syntaxin-11 and Munc18-2, also encoded by genes associated with FHL, were less correlated with cytotoxicity in lymphocyte subsets (Fig. 1, a and b). Thus, the data suggest an important role for induction of Munc13-4 expression in regulating the cytotoxic capacity of lymphocytes.
Affiliation: Centre for Infectious Medicine, Department of Medicine; Clinical Genetics Unit, Department of Molecular Medicine and Surgery, and Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden Division of Hematology, Oncology and Transplantation, University of Minnesota Cancer Center, Minneapolis, MN 55455.