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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

Authors :
Galgano, Donatella
Soheili, Tayebeh
Voss, Matthias
Torralba-Raga, Lamberto
Tesi, Bianca
Cichocki, Frank
Andre, Isabelle
Rettig, Jens
Cavazzana, Marina
Bryceson, Yenan
Karolinska Institutet [Stockholm]
Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163)
Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
Karolinska University Hospital [Stockholm]
University of Minnesota [MN, USA]
Saarland University [Saarbrücken]
CHU Necker - Enfants Malades [AP-HP]
Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
University of Bergen (UiB)
André, Isabelle
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.

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⟩