Human NK Cells Downregulate Zap70 and Syk in Response to Prolonged Activation or DNA Damage

Pugh, Jason L.; Nemat-Gorgani, Neda; Norman, Paul J.; Guethlein, Lisbeth A.; Parham, Peter

doi:10.4049/jimmunol.1700542

Cited by 13 publications

(14 citation statements)

References 68 publications

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“…NKs integrate a variety of signals received through their activating and inhibitory receptors (Kruse et al., 2014, Vivier et al., 2008). The first steps of this pathway are fairly well known, including, for example, the signaling molecules DAP12, ZAP70, and Syk (Jelencic et al., 2018, Pugh et al., 2018), but the later stages are less understood. IFNG-AS1 can now join the web of intracellular signaling at this phase of the immune response.…”

Section: Discussionmentioning

confidence: 99%

IFNG-AS1 Enhances Interferon Gamma Production in Human Natural Killer Cells

Stein¹,

Berhani²,

Schmiedel³

et al. 2019

iScience

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SummaryLong, non-coding RNAs (lncRNAs) are involved in the regulation of many cellular processes. The lncRNA IFNG-AS1 was found to strongly influence the responses to several pathogens in mice by increasing interferon gamma (IFNγ) secretion. Studies have looked at IFNG-AS1 in T cells, yet IFNG-AS1 function in natural killer cells (NKs), an important source of IFNγ, remains unknown. Here, we show a previously undescribed sequence of IFNG-AS1 and report that it may be more abundant in cells than previously thought. Using primary human NKs and an NK line with IFNG-AS1 overexpression, we show that IFNG-AS1 is quickly induced upon NK cell activation, and that IFNG-AS1 overexpression leads to increased IFNγ secretion. Taken together, our work expands IFNG-AS1's activity to the innate arm of the type I immune response, helping to explain its notable effect in animal models of disease.

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Section: Discussionmentioning

confidence: 99%

IFNG-AS1 Enhances Interferon Gamma Production in Human Natural Killer Cells

Stein¹,

Berhani²,

Schmiedel³

et al. 2019

iScience

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“…A prior study identified a subset of human NK cells that expressed low levels of the Zap70 and Syk kinases (Zap70 low Syk low ) and had decreased functional potential compared to Zap70 hi Syk hi NK cells. In addition, they showed that extended NK cell activation resulted in the loss of Zap70 and Syk (25). This suggests that extended NK cell activation leads to low levels of Syk and Zap70, resulting in decreased NK cell function.…”

Section: Resultsmentioning

confidence: 99%

Chronic Ly49H Receptor Engagement in vivo Decreases NK Cell Response to Stimulation Through ITAM-Dependent and Independent Pathways Both in vitro and in vivo

et al. 2019

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Natural killer (NK) cells play an important role in the innate immune response. The summation of activation and inhibitory signals delivered through cell surface membrane receptors determines NK cell function. However, the continuous engagement of an activating receptor on NK cells appears to render the cells hyporesponsive to stimulation through other unrelated activating receptors. The mechanism by which this takes place remains unclear. Herein we demonstrate that continuous in vivo engagement of the Ly49H receptor with its ligand, m157, results in Ly49H + NK cells that are hyporesponsive to further stimulation by other ITAM-dependent and independent receptors, while Ly49H − NK cells remain unaffected. The hyporesponsiveness of the NK cell correlates with the degree of Ly49H receptor downmodulation on its cell surface. We observe defects in calcium flux in the hyporesponsive NK cells following stimulation through the NK1.1 receptor. In addition, we observe differences in signaling molecules that play a role in calcium flux, including spleen tyrosine kinase (Syk) at baseline and phosphorylated phospholipase C gamma 2 (p-PLCγ2) at both baseline and following stimulation through NK1.1. We also demonstrate that various ITAM associated activation receptors, including Ly49H, remain associated with their respective adaptor molecules. With regard to in vivo NK cell function, we did not find differences in the formation of metastatic lung lesions following IV injection of B16 melanoma cells. However, we did observe defects in rejection of missing-self targets in vivo . The data suggest that continuous engagement of the Ly49H activating receptor on NK cells results in hyporesponsiveness of the NK cells to all of the ITAM-dependent and independent receptors we analyzed due to altered signaling pathways downstream of the receptor and adaptor molecule.

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“…However, to date, studies on the relationship between Syk and DNA breaks are limited. The only finding reported is that DNA damage and DNA double-strand breaks can suppress the expression of Syk in B [50] and NK cells [51].…”

Section: Discussionmentioning

confidence: 99%

Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation

Huang

Chen

et al. 2020

Cancers

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Syk is a non-receptor tyrosine kinase involved in the signalling of immunoreceptors and growth factor receptors. Previously, we reported that Syk mediates epidermal growth factor receptor (EGFR) signalling and plays a negative role in the terminal differentiation of keratinocytes. To understand whether Syk is a potential therapeutic target of cancer cells, we further elucidated the role of Syk in disease progression of squamous cell carcinoma (SCC), which is highly associated with EGFR overactivation, and determined the combined effects of Syk and PARP1 inhibitors on SCC viability. We found that pharmacological inhibition of Syk could attenuate the EGF-induced phosphorylation of EGFR, JNK, p38 MAPK, STAT1, and STAT3 in A431, CAL27 and SAS cells. In addition, EGF could induce a Syk-dependent IL-8 gene and protein expression in SCC. Confocal microscopic data demonstrated the ability of the Syk inhibitor to change the subcellular distribution patterns of EGFR after EGF treatment in A431 and SAS cells. Moreover, according to Kaplan-Meier survival curve analysis, higher Syk expression is correlated with poorer patient survival rate and prognosis. Notably, both Syk and EGFR inhibitors could induce PARP activation, and synergistic cytotoxic actions were observed in SCC cells upon the combined treatment of the PARP1 inhibitor olaparib with Syk or the EGFR inhibitor. Collectively, we reported Syk as an important signalling molecule downstream of EGFR that plays crucial roles in SCC development. Combining Syk and PARP inhibition may represent an alternative therapeutic strategy for treating SCC.

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Human NK Cells Downregulate Zap70 and Syk in Response to Prolonged Activation or DNA Damage

Cited by 13 publications

References 68 publications

IFNG-AS1 Enhances Interferon Gamma Production in Human Natural Killer Cells

IFNG-AS1 Enhances Interferon Gamma Production in Human Natural Killer Cells

Chronic Ly49H Receptor Engagement in vivo Decreases NK Cell Response to Stimulation Through ITAM-Dependent and Independent Pathways Both in vitro and in vivo

Synergistic Anti-Tumour Effect of Syk Inhibitor and Olaparib in Squamous Cell Carcinoma: Roles of Syk in EGFR Signalling and PARP1 Activation

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