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Alternative UNC13D Promoter Encodes a Functional Munc13-4 Isoform Predominantly Expressed in Lymphocytes and Platelets
Alternative UNC13D Promoter Encodes a Functional Munc13-4 Isoform Predominantly Expressed in Lymphocytes and Platelets
- Source :
- Frontiers in Immunology, Frontiers in Immunology, 2020, 11, ⟨10.3389/fimmu.2020.01154⟩, Frontiers in Immunology, 2020, 11 (7), pp.1662-1676. ⟨10.3389/fimmu.2020.01154⟩
- Publication Year :
- 2020
- Publisher :
- HAL CCSD, 2020.
-
Abstract
- International audience; Autosomal recessive mutations in genes required for cytotoxicity are causative of a life-threatening, early-onset hyperinflammatory syndrome termed familial hemophagocytic lymphohistiocytosis (FHL). Mutations in UNC13D cause FHL type 3. UNC13D encodes Munc13-4, a member of the Unc13 protein family which control SNARE complex formation and vesicle fusion. We have previously identified FHL3-associated mutations in the first intron of UNC13D which control transcription from an alternative transcriptional start site. Using isoform specific antibodies, we demonstrate that this alternative Munc13-4 isoform with a unique N-terminus is preferentially expressed in human lymphocytes and platelets, as compared to the conventional isoform that was mostly expressed in monocytes and neutrophils. The distinct N-terminal of the two isoforms did not impact on Munc13-4 localization or trafficking to the immunological synapse of cytotoxic T cells. Moreover, ectopic expression of both isoforms efficiently restored exocytosis by FHL3 patient-derived Munc13-4 deficient T cells. Thus, we demonstrate that the conventional and alternative Munc13-4 isoforms have different expression pattern in hematopoietic cell subsets, but display similar localization and contribution to T cell exocytosis. The use of an alternative transcriptional starting site (TSS) in lymphocytes and platelets could be selected for increasing the overall levels of Munc13-4 expression for efficient secretory granule release.
- Subjects :
- [SDV] Life Sciences [q-bio]
familial hemophagocytic lymphohistiocytosis type 3
lymphocyte cytotoxicity
[SDV]Life Sciences [q-bio]
Immunology
Immunology and Allergy
[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy
[SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy
UNC13D
intronic mutation
primary immunodeficiency
alternative intronic promoter/isoform
Subjects
Details
- Language :
- English
- ISSN :
- 16643224
- Database :
- OpenAIRE
- Journal :
- Frontiers in Immunology, Frontiers in Immunology, 2020, 11, ⟨10.3389/fimmu.2020.01154⟩, Frontiers in Immunology, 2020, 11 (7), pp.1662-1676. ⟨10.3389/fimmu.2020.01154⟩
- Accession number :
- edsair.dedup.wf.001..3a252de86beb13af3b29439efd6df191
- Full Text :
- https://doi.org/10.3389/fimmu.2020.01154⟩