Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/17387
Title: Bi-Allelic Mutations in STXBP2 Reveal a Complementary Role for STXBP1 in Cytotoxic Lymphocyte Killing.
Authors: Lopez, Jamie A;Noori, Tahereh;Minson, Adrian;Li Jovanoska, Lu;Thia, Kevin;Hildebrand, Michael S;Akhlaghi, Hedieh;Darcy, Phillip K;Kershaw, Michael H;Brown, Natasha J;Grigg, Andrew P;Trapani, Joseph A;Voskoboinik, Ilia
Affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia
Department of Clinical Haematology, Austin Health, Heidelberg, Victoria, Australia
Department of Medicine, Austin Health, Heidelberg, Victoria, Australia
Department of Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia
Issue Date: 2018
EDate: 2018-03-15
Citation: Frontiers in immunology 2018; 9: 529
Abstract: The ability of cytotoxic lymphocytes (CL) to eliminate virus-infected or cancerous target cells through the granule exocytosis death pathway is critical to immune homeostasis. Congenital loss of CL function due to bi-allelic mutations inPRF1, UNC13D, STX11, orSTXBP2leads to a potentially fatal immune dysregulation, familial haemophagocytic lymphohistiocytosis (FHL). This occurs due to the failure of CLs to release functional pore-forming protein perforin and, therefore, inability to kill the target cell. Bi-allelic mutations in partner proteinsSTXBP2orSTX11impair CL cytotoxicity due to failed docking/fusion of cytotoxic secretory granules with the plasma membrane. One unique feature of STXBP2- and STX11-deficient patient CLs is that their short-termin vitrotreatment with a low concentration of IL-2 partially or completely restores natural killer (NK) cell degranulation and cytotoxicity, suggesting the existence of a secondary, yet unknown, pathway for secretory granule exocytosis. In the current report, we studied NK and T-cell function in an individual with late presentation of FHL due to hypomorphic bi-allelic mutations inSTXBP2. Intriguingly, in addition to the expected alterations in the STXBP2 and STX11 proteins, we also observed a concomitant significant reduction in the expression of homologous STXBP1 protein and its partner STX1, which had never been implicated in CL function. Further analysis of human NK and T cells demonstrated a functional role for the STXBP1/STX1 axis in NK and CD8+ T-cell cytotoxicity, where it appears to be responsible for as much as 50% of their cytotoxic activity. This discovery suggests a unique and previously unappreciated interplay between STXBP/Munc proteins regulating the same essential granule exocytosis pathway.
URI: http://ahro.austin.org.au/austinjspui/handle/1/17387
DOI: 10.3389/fimmu.2018.00529
ORCID: 0000-0003-2739-0515
PubMed URL: 29599780
ISSN: 1664-3224
Type: Journal Article
Subjects: Munc18-1
Munc18-2
apoptosis
cytotoxic T cells
cytotoxic lymphocytes
familial haemophagocytic lymphohistiocytosis
immunodeficiency
natural killer cells
Appears in Collections:Journal articles

Files in This Item:
There are no files associated with this item.


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.