The IL-15–AKT–XBP1s signaling pathway contributes to effector functions and survival in human NK cells

Wang, Yufeng; Zhang, Hongjie; Yi, Ping; Dong, Wenjuan; Nalin, Ansel P.; Zhang, Jianying; Zhu, Zheng; Chen, Lichao; Benson, Don M.; Mundy-Bosse, Bethany L.; Freud, Aharon G.; Caligiuri, Michael A.; Yu, Jianhua

doi:10.1038/s41590-018-0265-1

Cited by 93 publications

(103 citation statements)

References 48 publications

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“…This could indicate that T-bet plays a role in triggering cytotoxicity programs in the cells, potentially downstream of IL-15 signaling. This notion is supported by Wang et al ( 30 ), who demonstrated a signaling pathway linking IL-15 and T-bet in human NK cells. They showed that IL-15 bound to IL-15Rα triggered the phosphorylation of Akt, which in turn led to the de-ubiquitination of transcription factor functionally spliced X-box binding protein 1 (XBP1s).…”

Section: Discussionmentioning

confidence: 63%

“…This strongly points toward a positive effect of IL-15 on cell survival and function in these two cell types. Indeed, the IL-15 signaling pathway has recently been shown to directly contribute to effector functions in human NK cells ( 30 ). Despite these encouraging indications, few attempts have been made to test the influence of IL-15 on Vγ9Vδ2 T cell expansion ( 31 , 32 ).…”

Section: Introductionmentioning

confidence: 99%

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Expansion With IL-15 Increases Cytotoxicity of Vγ9Vδ2 T Cells and Is Associated With Higher Levels of Cytotoxic Molecules and T-bet

et al. 2020

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Cancer immunotherapy has shown great advances during recent years, but it has yet to reach its full potential in all cancer types. Adoptive cell therapy (ACT) is now an approved treatment option for certain hematological cancers and has also shown success for some solid cancers. Still, benefit and eligibility do not extend to all patients. ACT with Vγ9Vδ2 T cells is a promising approach to overcome this hurdle. In this study, we aimed to explore the effect of different cytokine conditions on the expansion of Vγ9Vδ2 T cells in vitro . We could show that Vγ9Vδ2 T cell expansion is feasible with two different cytokine conditions: (a) 1,000 U/ml interleukin (IL)-2 and (b) 100 U/ml IL-2 + 100 U/ml IL-15. We did not observe differences in expansion rate or Vγ9Vδ2 T cell purity between the conditions; however, IL-2/IL-15-expanded Vγ9Vδ2 T cells displayed enhanced cytotoxicity against tumor cells, also in hypoxia. While this increase in killing capacity was not reflected in natural killer (NK) cell marker or activation marker expression, we demonstrated that IL-2/IL-15-expanded Vγ9Vδ2 T cells were characterized by an increased expression of perforin, granzyme B, and granulysin compared to IL-2-expanded cells. These cytotoxic molecules were not only increased in a resting state, but also released to a greater extent upon target recognition. In contrast, CD107a and cytokine expression did not differ between expansion conditions. However, IL-2/IL-15-expanded Vγ9Vδ2 T cells showed higher levels of transcription factor T-bet expression, which could indicate that T-bet and cytotoxic molecule levels confer the increased cytotoxicity. These results advocate the inclusion of IL-15 into ex vivo Vγ9Vδ2 T cell expansion protocols in future clinical studies.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Expansion With IL-15 Increases Cytotoxicity of Vγ9Vδ2 T Cells and Is Associated With Higher Levels of Cytotoxic Molecules and T-bet

et al. 2020

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“…The oncogenic roles of XBP1 in CRC and other types of cancer have been reported in numerous studies; the activation of the IRE1/XBP1 pathway induced cell proliferation and invasion in CRC 3, whereby XBP1 was demonstrated to promote with poor prognosis (24); in breast cancer, the expression levels of XBP1s in the nucleus were correlated with shorter survival (25); whereas in ovarian cancer, the IRE1/XBP1 signaling pathway controlled T-cell functions, thus, mediating ER stress or targeting the IRE1/XBP1 pathway may restore the antitumor ability of T-cells (26). In addition, XBP1 positively regulated the cytolytic activity of human natural killer cells against leukemia cells (27); in hepatocellular carcinoma, the IRE1/XBP1 pathway controlled the expression of interleukin-6 (IL-6) and promoted hepatocarcinoma progression (28); and in oropharyngeal carcinoma without papillomavirus, the IRE1/XBP1 pathway induced resistance to radiotherapy by mediating IL-6 production (29). Thus, the transcription factor XBP1 may be a potential target to mediate tumor immunology and block cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1

Jiang

Wang

et al. 2020

Oncol Rep

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Colorectal cancer (CRC) is the third most common tumor in the world; however, the role and mechanism of endoplasmic reticulum (ER) stress in CRC metastasis remains largely unclear. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA), which has previously been associated with CRC metastasis. It has been suggested that ER stress pathways regulate lncRNA expression; however, the effect of ER stress on MALAT1 expression in cancer is unknown. The present study aimed to investigate the relationship between ER stress pathways, MALAT1 expression and cell migration in CRC cells. ER stress was induced by thapsigargin (TG); low dose TG induced the migration of HT29 and HCT116 cells, but not SW1116 and SW620 cells. This effect was associated with increased expression levels of MALAT1, as the knockdown of MALAT1 prevented TG-induced cell migration. TG-induced MALAT1 expression was associated with inositol-requiring enzyme 1 (IRE1) expression and activation of the protein kinase R (PKR)-like ER kinase (PERK) signaling pathway. X-box-binding protein 1 (XBP1) and activating transcription factor 4 (ATF4) binding sites were predicted to be located in the MALAT1 gene promoter regions and the expression of MALAT1 was positively associated with XBP1 and ATF4 expression levels in CRC tissue samples. Thus, these findings indicated that ER stress may promote the migration of CRC cells and contribute to the progression of CRC through the activation of the IRE1/XBP1 and PERK/eIF2α/ATF4 signaling pathways. In conclusion, to the best of our knowledge, this study is the first report that lncRNA MALAT1 expression is regulated by the IRE1/XBP1 pathway in CRC.

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“…Interestingly, this study mapped amino acid residues 227-252 of XBP1s as required for its interaction with PGC1α (Lee et al 2018), distinct from residues 301-371, which are required to interact with SHP. Very recently, another study showed that XBP1s ubiquitination and protein stability in natural killer cells are modulated in response to interleukin-15 signaling (Wang et al 2019). An outstanding question has been the nature of the E3 ligase that mediates XBP1s degradation.…”

Section: Discussionmentioning

confidence: 99%

“…XBP1s transcriptional activity can be regulated further by posttranslational modifications such as phosphorylation, acetylation, and sumoylation Wang et al 2011;Liu et al 2016). Moreover, a recent study showed that XBP1s protein stability can also be modulated in natural killer cells in response to interleukin-15 signaling (Wang et al 2019). How XBP1s protein is degraded in other cell types or tissues remains unclear.…”

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confidence: 99%

The orphan nuclear receptor SHP regulates ER stress response by inhibiting XBP1s degradation

et al. 2019

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The orphan nuclear receptor SHP (small heterodimer partner) is a well-known transcriptional corepressor of bile acid and lipid metabolism in the liver; however, its function in other tissues is poorly understood. Here, we report an unexpected role for SHP in the exocrine pancreas as a modulator of the endoplasmic reticulum (ER) stress response. SHP expression is induced in acinar cells in response to ER stress and regulates the protein stability of the spliced form of X-box-binding protein 1 (XBP1s), a key mediator of ER stress response. Loss of SHP reduces XBP1s protein level and transcriptional activity, which in turn attenuates the ER stress response during the fasting-feeding cycle.Consequently, SHP-deficient mice also are more susceptible to cerulein-induced pancreatitis. Mechanistically, we show that SHP physically interacts with the transactivation domain of XBP1s, thereby inhibiting the polyubiquitination and degradation of XBP1s by the Cullin3-SPOP (speckle-type POZ protein) E3 ligase complex. Together, our data implicate SHP in governing ER homeostasis and identify a novel posttranslational regulatory mechanism for the key ER stress response effector XBP1.

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The IL-15–AKT–XBP1s signaling pathway contributes to effector functions and survival in human NK cells

Cited by 93 publications

References 48 publications

Expansion With IL-15 Increases Cytotoxicity of Vγ9Vδ2 T Cells and Is Associated With Higher Levels of Cytotoxic Molecules and T-bet

Expansion With IL-15 Increases Cytotoxicity of Vγ9Vδ2 T Cells and Is Associated With Higher Levels of Cytotoxic Molecules and T-bet

Thapsigargin promotes colorectal cancer cell migration through upregulation of lncRNA MALAT1

The orphan nuclear receptor SHP regulates ER stress response by inhibiting XBP1s degradation

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