Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency

Cichocki, Frank; Schlums, Heinrich; Li, Hongchuan; Stache, Vanessa; Holmes, Timothy; Lenvik, Todd; Chiang, Samuel C.C.; Miller, Jeffrey S.; Meeths, Marie; Anderson, Stephen; Bryceson, Yenan T.

doi:10.1084/jem.20131131

Cited by 38 publications

(30 citation statements)

References 41 publications

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“…This may be particularly relevant to MAS in the setting of sJIA where IL-6 is often elevated, and heterozygous fHLH gene mutations are frequently present in those with MAS (15). Nevertheless, one cannot formally rule-out the possibility of not identifying other contributory genes leading to decreased NK cell function, or not identifying causative mutations or deletions in non-coding portions of HLH genes among sHLH and MAS patients (46). However, the fact that isolated over-expression of the Rab27A p.A87P mutation in a NK-92 cell possessing the Rab27A WT gene is able to delay granzyme B polarization to the immunologic synapse (Figure 8) and decrease NK cell lytic function (Figure 2) argues these genes may directly contribute to HLH pathophysiology as single copy mutations.…”

Section: Discussionmentioning

confidence: 99%

A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis

Zhang

Bracaglia

Prencipe

et al. 2016

The Journal of Immunology

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Frequently fatal, primary hemophagocytic lymphohistiocytosis (HLH) occurs in infancy resulting from homozygous mutations in natural killer (NK) and CD8 T cell cytolytic pathway genes. Secondary HLH presents after infancy and may be associated with heterozygous mutations in HLH genes. We report 2 unrelated teenagers with HLH and an identical heterozygous RAB27A mutation (c.259G>C). We explore the contribution of this Rab27A missense (p.A87P) mutation on NK cell cytolytic function by cloning it into a lentiviral expression vector prior to introduction into the human NK-92 cell line. NK cell degranulation (CD107a expression), target cell conjugation, and K562 target cell lysis was compared between mutant and wild-type transduced NK-92 cells. Polarization of granzyme B to the immunologic synapse and interaction of mutant Rab27A (p.A87P) with Munc13-4 were explored by confocal microscopy and proximity ligation assay, respectively. Over-expression of the RAB27A mutation had no effect on cell conjugate formation between the NK and target cells but decreased NK cell cytolytic activity and degranulation. Moreover, the mutant Rab27A protein decreased binding to Munc13-4 and delayed granzyme B polarization towards the immunologic synapse. This heterozygous RAB27A mutation blurs the genetic distinction between primary and secondary HLH by contributing to HLH via a partial dominant-negative effect.

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Section: Discussionmentioning

confidence: 99%

A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis

Zhang

Bracaglia

Prencipe

et al. 2016

The Journal of Immunology

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“…Furthermore, loss of WASp-interacting protein functions causes defects in NK cell–mediated killing via increased proteasome-mediated WASp degradation and its mislocalization (32, 34–37). Lastly, inefficient tethering of lytic granules to the plasma membrane in NK cells carrying mutations in the UNC13D gene is associated with a complete loss of NK cell–mediated cytotoxicity (11, 38–41). …”

Section: Discussionmentioning

confidence: 99%

“…A number of cytoskeletal-associated proteins including Wiskott-Aldrich-Syndrome protein (WASp), WASp-interacting protein, cofilin, Munc13-4, and nonmuscle myosin IIA (NMIIA) are involved in the stepwise cytoskeletal reorganization that is requisite for lytic granule release (3, 6, 9, 10). Mutations in the genes coding for these proteins severely compromise NK cell-mediated cytotoxicity and result in severe immunodeficiency (11, 12). …”

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confidence: 99%

UNC-45A Is a Nonmuscle Myosin IIA Chaperone Required for NK Cell Cytotoxicity via Control of Lytic Granule Secretion

Iizuka

Cichocki

Sieben

et al. 2015

The Journal of Immunology

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NK cell’s killing is a tightly regulated process under the control of specific cytoskeletal proteins. This includes Wiskott-Aldrich-Syndrome protein, Wiskott-Aldrich-Syndrome protein-interacting protein, cofilin, Munc13-4, and nonmuscle myosin IIA (NMIIA). These proteins play a key role in controlling NK-mediated cytotoxicity either via regulating the attachment of lytic granules to the actin-based cytoskeleton or via promoting the cytoskeletal reorganization that is requisite for lytic granule release. UNC-45A is a highly conserved member of the UNC-45/CRO1/She4p family of proteins that act as chaperones for both conventional and nonconventional myosin. Although we and others have shown that in lower organisms and in mammalian cells NMIIA-associated functions, such as cytokinesis, cell motility, and organelle trafficking, are dependent upon the presence of UNC-45A, its role in NK-mediated functions is largely unknown. In this article, we describe UNC-45A as a key regulator of NK-mediated cell toxicity. Specifically we show that, in human NK cells, UNC-45A localize at the NK cell immunological synapse of activated NK cells and is part of the multiprotein complex formed during NK cell activation. Furthermore, we show that UNC-45A is disposable for NK cell immunological synapse formation and lytic granules reorientation but crucial for lytic granule exocytosis. Lastly, loss of UNC-45A leads to reduced NMIIA binding to actin, suggesting that UNC-45A is a crucial component in regulating human NK cell cytoskeletal dynamics via promoting the formation of actomyosin complexes.

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“…The Ifng (IFN-γ) and Tbx21 (T-bet) gene loci in NK cells and Th1 cells are among the better-known targets of STAT4 (Good et al 2009;Mullen et al 2001;Oestreich and Weinmann 2012;Schoenborn et al 2007;Thieu et al 2008;Zhang and Boothby 2006). Specifically in NK cells, other recently identified STAT4 targets include miR-155, which was shown to regulate homeostasis and survival of NK cells by targeting Noxa and SOCS1 in a stage-specific manner (Zawislak et al 2013); the adaptor protein MyD88, which signals downstream from the IL-18 receptor to promote NK cell proliferation and IFN-γ secretion (Madera and Sun 2015); the proliferation-inducing transcription factor Zbtb32 (Beaulieu et al 2014), whose function will be discussed in greater detail below; munc13-4 (encoded by the UNC13D gene), whose expression is required for exocytosis of lytic granules by NK cells and CD8+ T cells (Cichocki et al 2014); perforin (Yamamoto et al 2002;Yu et al 1999) andIL-10 (Grant et al 2008). Future ChIP-seq analysis in activated NK cells will reveal additional gene targets of STAT4.…”

Section: Transcriptional Control Of Nk Cell Activation and Functionmentioning

confidence: 99%

Transcriptional Control of NK Cells

Sun

2015

Natural Killer Cells

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Natural killer (NK) cells are innate lymphocytes that survey the environment and protect the host from infected and cancerous cells. As their name implies, NK cells represent an early line of defense during pathogen invasion by directly killing infected cells and secreting inflammatory cytokines. Although the function of NK cells was first described more than four decades ago, the development of this cytotoxic lineage is not well understood. In recent years, we have begun to identify specific transcription factors that control each stage of development and maturation, from ontogeny of the NK cell progenitor to the effector functions of activated NK cells in peripheral organs. This chapter highlights the transcription factors that are unique to NK cells, or shared between NK cells and other hematopoietic cell lineages, but govern the biology of this cytolytic lymphocyte.

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Transcriptional regulation of Munc13-4 expression in cytotoxic lymphocytes is disrupted by an intronic mutation associated with a primary immunodeficiency

Abstract: A conserved regulatory element in intron 1 of UNC13D regulates Munc13-4 expression.

Cited by 38 publications

References 41 publications

A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis

A Heterozygous RAB27A Mutation Associated with Delayed Cytolytic Granule Polarization and Hemophagocytic Lymphohistiocytosis

UNC-45A Is a Nonmuscle Myosin IIA Chaperone Required for NK Cell Cytotoxicity via Control of Lytic Granule Secretion

Transcriptional Control of NK Cells

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