Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via TNFR1 Receptor

Yashin, Denis V.; Ivanova, Olga K.; Soshnikova, Natalia; Sheludchenkov, Anton A.; Романова, Е. А.; Dukhanina, E. A.; Tonevitsky, Alexander G.; Гнучев, Н. В.; Gabibov, Alexander; Georgiev, G.P.; Sashchenko, Lidia P.

doi:10.1074/jbc.m115.639732

Cited by 53 publications

(49 citation statements)

References 33 publications

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“…The cytotoxicity of the medium conditioned by CD8+ lymphocytes on L929 cells was also completely suppressed by anti‐Tag7 and anti‐Hsp70 antibodies, suggesting the dependence of cytotoxic effect on the presence of Tag7–Hsp70 complex in the medium. In view of our data that this complex induces cell death pathways by interacting with the TNFR1 receptor , we performed experiments with anti‐TNFR1 antibodies and found that they also inhibited the cytotoxic effect on L929 cells, confirming that the medium conditioned by CD8+ lymphocytes contained the Tag7–Hsp70 complex (Fig. B).…”

Section: Resultssupporting

confidence: 52%

Tilorone activates NK cells and cytotoxic lymphocytes that kill HLA‐negative tumor cells

et al. 2018

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Tilorone hydrochloride, a low‐molecular‐weight synthetic compound, induces interferon production and has been reported to have both antiviral and antitumor activities. Here, we have demonstrated the ability of tilorone to activate NK cells and specific subpopulations of cytotoxic CD4+ and CD8+ T lymphocytes that recognize immune‐evasive tumor cells and kill them via the FasL–Fas interaction. We have also performed a comparative analysis of characteristics between lymphocytes activated in the fraction of human peripheral blood mononuclear cells (PBMCs) upon treatment with different stimulants of the immune response: tilorone, innate immunity protein Tag7, and cytokine IL‐2, a regulator of adaptive immunity. The results show that all the three stimulants, regardless of their nature, activate lymphocytes that are identical with respect to the spectrum of target cells, phenotype, and mechanism of cytotoxic action However, these stimulants induce different mechanisms of lymphocyte activation at early stages of the immune response. © 2018 IUBMB Life, 71(3):376–384, 2019

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Section: Resultssupporting

confidence: 52%

Tilorone activates NK cells and cytotoxic lymphocytes that kill HLA‐negative tumor cells

et al. 2018

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“…The Fas receptor belongs to the family of cell death receptors that have been shown to switch between alternative signaling processes. In our experiments on the cytotoxic effect of the Tag7-Hsp70 complex, which is a ligand for the TNF-R1 receptor, the blocking of apoptosis with inhibitors of caspases 3 and 8 resulted in activation of the RIP1dependent necroptosis [Yashin et al, 2015]. In this study, the number of cells dying by way of necroptosis (after 20-h incubation with lymphocytes) has not increased after the inhibition of apoptosis (cell death after 3 h).…”

Section: Discussionmentioning

confidence: 53%

CD3⁺CD8⁺NKG2D⁺ T Lymphocytes Induce Apoptosis and Necroptosis in HLA‐Negative Cells via FasL–Fas Interaction

Ivanova¹,

Sharapova²,

Романова³

et al. 2017

J of Cellular Biochemistry

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An important problem in cellular immunology is to identify new populations of cytotoxic lymphocytes capable of killing tumor cells that have lost classical components of MHC-machinery and to understand mechanisms of the death of these cells. We have previously found that CD4 CD25 lymphocytes appear in the lymphokine-activated killer (LAK) cell culture, which carry Tag7 (PGRP-S) and FasL proteins on their surface and can kill Hsp70- and Fas-expressing HLA-negative cells. In this work, we have continued to study the mechanisms of killing of the HLA-negative tumor cells, focusing this time on the CD8 lymphocytes. We show that after a tumor antigen contact the IL-2 activated CD8 lymphocytes acquire ability to lyse tumor cells bearing this antigen. However, activation of the CD8 lymphocytes in the absence of antigen causes appearance of a cytotoxic population of CD8 NKG2D lymphocytes, which are able to lyse HLA-negative cancer cells that have lost the classic mechanism of antigen presentation. These cells recognize the noncanonical MicA antigen on the surface of HLA-negative K562 cells but kill them via the FasL-Fas interaction, as do cytotoxic T lymphocytes. FasL presented on the lymphocyte surface can trigger both apoptosis and necroptosis. Unlike in the case of TNFR1, another cell death receptor, no switching to alternative processes has been observed upon induction of Fas-dependent cell death. It may well be that the apoptotic and necroptotic signals are transduced separately in the latter case, with the ability of FasL lymphocytes to induce necroptosis allowing them to kill tumor cells that escape apoptosis. J. Cell. Biochem. 118: 3359-3366, 2017. © 2017 Wiley Periodicals, Inc.

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“…Another promising strategy for reduction of inflammation in the autoimmune diseases is to develop agents preventing signal transduction through the TNF-TNFR1 system [14]. For example, we have recently demonstrated that innate immunity regulator Tag7 can bind to the TNFR1 protein, a specific TNF receptor [15].…”

Section: Introductionmentioning

confidence: 99%

A 12-mer Peptide of Tag7 (PGLYRP1) Forms a Cytotoxic Complex with Hsp70 and Inhibits TNF-Alpha Induced Cell Death

Романова

Sharapova

Telegin

et al. 2020

Cells

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Investigation of interactions between a pro-inflammatory cytokine tumor necrosis factor (TNFα) and its receptor is required for the development of new treatments for autoimmune diseases associated with the adverse effects of TNFα. Earlier, we demonstrated that the innate immunity protein Tag7 (PGRP-S, PGLYRP1) can interact with the TNFα receptor, TNFR1, and block the transduction of apoptotic signals through this receptor. A complex formed between the Tag7 protein and the major heat shock protein Hsp70 can activate TNFR1 receptor and induce tumor cell death via either apoptotic or necroptotic pathway. In this study, we show that a 12-mer peptide, designated 17.1, which was derived from the Tag7 protein, can be regarded as a novel TNFα inhibitor, also is able to form a cytotoxic complex with the heat shock protein Hsp70. This finding demonstrates a new role for Hsp70 protein in the immune response. Also, this new inhibitory 17.1 peptide demonstrates an anti-inflammatory activity in the complete Freund’s adjuvant (CFA)-induced autoimmune arthritis model in laboratory mice. It appears that the 17.1 peptide could potentially be used as an anti-inflammatory agent.

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Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via TNFR1 Receptor

Cited by 53 publications

References 33 publications

Tilorone activates NK cells and cytotoxic lymphocytes that kill HLA‐negative tumor cells

Tilorone activates NK cells and cytotoxic lymphocytes that kill HLA‐negative tumor cells

CD3⁺CD8⁺NKG2D⁺ T Lymphocytes Induce Apoptosis and Necroptosis in HLA‐Negative Cells via FasL–Fas Interaction

A 12-mer Peptide of Tag7 (PGLYRP1) Forms a Cytotoxic Complex with Hsp70 and Inhibits TNF-Alpha Induced Cell Death

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Tag7 (PGLYRP1) in Complex with Hsp70 Induces Alternative Cytotoxic Processes in Tumor Cells via TNFR1 Receptor

Cited by 53 publications

References 33 publications

Tilorone activates NK cells and cytotoxic lymphocytes that kill HLA‐negative tumor cells

Tilorone activates NK cells and cytotoxic lymphocytes that kill HLA‐negative tumor cells

CD3+CD8+NKG2D+ T Lymphocytes Induce Apoptosis and Necroptosis in HLA‐Negative Cells via FasL–Fas Interaction

A 12-mer Peptide of Tag7 (PGLYRP1) Forms a Cytotoxic Complex with Hsp70 and Inhibits TNF-Alpha Induced Cell Death

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CD3⁺CD8⁺NKG2D⁺ T Lymphocytes Induce Apoptosis and Necroptosis in HLA‐Negative Cells via FasL–Fas Interaction