BAT3 Regulates Mycobacterium tuberculosis Protein ESAT-6-Mediated Apoptosis of Macrophages

Grover, Ajay; Izzo, Angelo A.

doi:10.1371/journal.pone.0040836

Cited by 38 publications

(32 citation statements)

References 36 publications

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“…It has been shown that BAT3/BAG6 can be released from tumor cells in response to stress signals [42]. Both BAT3/ BAG6 as well as UBD/FAT10 expression was shown to be increased during inflammatory response [21,43]. This may be caused by the release of proinflammatory factors from macrophages of THRLBCL [12].…”

Section: Discussionmentioning

confidence: 99%

Nodular Lymphocyte Predominant Hodgkin Lymphoma and T cell/Histiocyte Rich Large B Cell Lymphoma Endpoints of a Spectrum of one Disease?

Hartmann¹,

Döring²,

Jakobus³

et al. 2014

Klin Padiatr

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In contrast to the commonly indolent clinical behavior of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), T cell/histiocyte rich large B cell lymphoma (THRLBCL) is frequently diagnosed in advanced clinical stages and has a poor prognosis. Besides the different clinical presentations of these lymphoma entities, there are variants of NLPHL with considerable histopathologic overlap compared to THRLBCL. Especially THRLBCL-like NLPHL, a diffuse form of NLPHL, often presents a histopathologic pattern similar to THRLBCL, suggesting a close relationship between both lymphoma entities. To corroborate this hypothesis, we performed gene expression profiling of microdissected tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. In unsupervised analyses, the lymphomas did not cluster according to their entity. Moreover, even in supervised analyses, very few consistently differentially expressed transcripts were found, and for these genes the extent of differential expression was only moderate. Hence, there are no clear and consistent differences in the gene expression of the tumor cells of NLPHL, THRLBCL-like NLPHL and THRLBCL. Based on the gene expression studies, we identified BAT3/ BAG6, HIGD1A, and FAT10/UBD as immunohistochemical markers expressed in the tumor cells of all three lymphomas. Characterization of the tumor microenvironment for infiltrating T cells and histiocytes revealed significant differences in the cellular composition between typical NLPHL and THRLBCL cases. However, THRLBCL-like NLPHL presented a histopathologic pattern more related to THRLBCL than NLPHL. In conclusion, NLPHL and THRLBCL may represent a spectrum of the same disease. The different clinical behavior of these lymphomas may be strongly influenced by differences in the lymphoma microenvironment, possibly related to the immune status of the patient at the timepoint of diagnosis.

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Section: Discussionmentioning

confidence: 99%

Nodular Lymphocyte Predominant Hodgkin Lymphoma and T cell/Histiocyte Rich Large B Cell Lymphoma Endpoints of a Spectrum of one Disease?

Hartmann¹,

Döring²,

Jakobus³

et al. 2014

Klin Padiatr

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“…With NKp30 activated by BAG6, we identified one important factor critically involved in RIG-I-induced EV-mediated antitumor activity in the human system. However, since NKp30 is a pseudogene in the murine system and is not expressed as a functional receptor, the RIG-I-EVs mediated NK activating effects in vivo might be mediated by unknown receptors distinct from NKp30 that have been reported to exist in mice but which have not been identified yet 45 . Thus, further work is needed to analyze the role of RIG-I induced EVs and BAG6 in the mouse model.…”

Section: Discussionmentioning

confidence: 99%

RIG-I activation induces the release of extracellular vesicles with antitumor activity

et al. 2016

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Activation of the innate immune receptor retinoic acid-inducible gene I (RIG-I) by its specific ligand 5′-triphosphate-RNA (3pRNA) triggers antitumor immunity predominantly via NK cell activation and direct apoptosis induction in tumor cells. However, how NK cells are mobilized to attack the tumor cells remains elusive. Here, we show that RIG-I activation induced the secretion of extracellular vesicles (EVs) from melanoma cells, which by themselves revealed antitumor activity in vitro and in vivo. RIG-I-induced EVs from melanoma cells exhibited an increased expression of the NKp30-ligand (BAG6, BAT3) on their surface triggering NK cell-mediated lysis of melanoma cells via activation of the cytotoxicity NK cell-receptor NKp30. Moreover, systemic administration of RIG-I-induced melanoma-EVs showed a potent antitumor activity in a melanoma mouse model in vivo. In conclusion, our data establish a new RIG-I-dependent pathway leading to NK cell-mediated tumor cell killing.

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“…[21][22][23] Under certain conditions and by mechanisms that are not completely understood, BAG6 can be released from cells into the extracellular environment. 10,24,25 The protein can be expressed on the surface Submitted January 7, 2013; accepted February 26, 2013. Prepublished online as Blood First Edition paper, March 18, 2013; DOI 10.1182 DOI 10.…”

Section: Introductionmentioning

confidence: 99%

“…[21][22][23] Under certain conditions and by mechanisms that are not completely understood, BAG6 can be released from cells into the extracellular environment. 10,24,25 The protein can be expressed on the surface of exosomes to engage NKp30 and to activate NK cells. 10,25 Exosomes are 50 to 100 nm microvesicles that originate from intracellular multivesicular bodies and are produced by many cell types.…”

Section: Introductionmentioning

confidence: 99%

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

Reiners¹,

Topolar²,

Henke³

et al. 2013

Blood

190

171

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Key Points• Exosomal NKp30-ligand BAG6 is crucial for detection of tumor cells by NK cells in vitro and in vivo.• Soluble plasma factors including BAG6 suppress NK cell cytotoxicity and promote evasion of CLL cells from NK cell anti-tumor activity.Natural killer (NK) cells are a major component of the anti-tumor immune response. NK cell dysfunctions have been reported in various hematologic malignancies, including chronic lymphocytic leukemia (CLL). Here we investigated the role of tumor cellreleased soluble and exosomal ligands for NK cell receptors that modulate NK cell activity. Soluble CLL plasma factors suppressed NK cell cytotoxicity and downregulated the surface receptors CD16 and CD56 on NK cells of healthy donors. The inhibition of NK cell cytotoxicity was attributed to the soluble ligand BAG6/BAT3 that engages the activating receptor NKp30 expressed on NK cells. Soluble BAG6 was detectable in the plasma of CLL patients, with the highest levels at the advanced disease stages. In contrast, NK cells were activated when BAG6 was presented on the surface of exosomes. The latter form was induced in non-CLL cells by cellular stress via an nSmase2-dependent pathway. Such cells were eliminated by lymphocytes in a xenograft tumor model in vivo. Here, exosomal BAG6 was essential for tumor cell killing because BAG6-deficient cells evaded immune detection. Taken together, the findings show that the dysregulated balance of exosomal vs soluble BAG6 expression may cause immune evasion of CLL cells. (Blood. 2013;121(18):3658-3665) IntroductionChronic lymphocytic leukemia (CLL) patients suffer from severe immune defects resulting in increased susceptibility to infections and failure to generate an anti-tumor immune response. 1 Natural killer (NK) cells, lymphocytes of the innate immune system, are considered to be a major component of the immunosurveillance in leukemia. [2][3][4] However, little is known about the functionality of NK cells and their role in tumor immune escape in CLL.NK cells are tightly regulated by inhibitory or activating "missing self" and "induced self" signals sensed via cell surface receptors. 5 The best examined activating receptors are the Fc receptor CD16, NKG2D, and the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. Known ligands for NKG2D are the major histocompatibility complex (MHC) class I-related molecules MICA/B and the UL16-binding proteins (ULBP1, ULBP2, ULBP3, ULBP4, ULBP5, and ULBP6) that are induced upon cellular stress on target cells. 6,7 Only a few ligands for the NCRs have been identified to date. [8][9][10][11][12][13][14] Surprisingly, among novel ligands for NKp30 (BAG6 [BAT3], 10 B7-H6 11 ), NKp44 (proliferating cell nuclear antigen 12 ) and NKp46 (vimentin 13,14 ), only B7-H6 is a surface membrane ligand. BAG6, proliferating cell nuclear antigen, and vimentin are proteins without any classical transmembrane domain and are known to exert divergent intracellular functions, including protein sorting and transport, proliferation, and apoptosis. It is still ...

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BAT3 Regulates Mycobacterium tuberculosis Protein ESAT-6-Mediated Apoptosis of Macrophages

Cited by 38 publications

References 36 publications

Nodular Lymphocyte Predominant Hodgkin Lymphoma and T cell/Histiocyte Rich Large B Cell Lymphoma Endpoints of a Spectrum of one Disease?

Nodular Lymphocyte Predominant Hodgkin Lymphoma and T cell/Histiocyte Rich Large B Cell Lymphoma Endpoints of a Spectrum of one Disease?

RIG-I activation induces the release of extracellular vesicles with antitumor activity

Soluble ligands for NK cell receptors promote evasion of chronic lymphocytic leukemia cells from NK cell anti-tumor activity

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