Ceramide synthesis regulates T cell activity and GVHD development

Sofi, M. Hanief; Heinrichs, Jessica; Dany, Mohammed; Nguyen, Hung; Dai, Min; Bastian, David; Schutt, Steven; Wu, Yongxia; Daenthanasanmak, Anusara; Gencer, Salih; Živković, Aleksandra; Szulc, Zdzisław M.; Stark, Holger; Liu, Chen; Chang, Yuan; Öğretmen, Besim; Yu, Xue-Zhong

doi:10.1172/jci.insight.91701

Cited by 53 publications

(46 citation statements)

References 55 publications

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“…The antimetastatic effects of CerS4/ceramide appear to be tumor-intrinsic because only disruption of CerS4-dependent ceramide metabolism within the tumor cells but not systemically in the tumor hosts caused an increase in metastatic incidence. A recent study also showed that genetic loss of CerS4 had no effect on T cell function and phenotype, a critical factor in tumor progression (65). However, the same study showed that mice deficient in another ceramide synthase, CerS6, showed global impairment in their T cell responses to allogeneic hematopoietic stem cell transplantation.…”

Section: Discussionmentioning

confidence: 99%

TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis

et al. 2017

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Signaling by the transforming growth factor–β (TGF-β) receptors I and II (TβRI/II) and the primary cilia-localized sonic hedgehog (Shh) pathway promote cell migration and, consequently, tumor metastasis. In contrast, the sphingolipid ceramide inhibits cell proliferation and tumor metastasis. We investigated whether ceramide metabolism inhibited TβRI/II trafficking to primary cilia to attenuate cross-talk between TβRI/II and the Shh pathway. We found that ceramide synthase 4 (CerS4)–generated ceramide stabilized the association between TβRI and the inhibitory factor Smad7, which limited the trafficking of TβRI/II to primary cilia. Expression of a mutant TβRI that signals but does not interact with Smad7 prevented the CerS4-mediated inhibition of migration in various cancer cells. Genetic deletion or knockdown of CerS4 prevented the formation of the Smad7-TβRI inhibitory complex and increased the association between TβRI and the transporter Arl6 through a previously unknown cilia-targeting signal (Ala31Thr32Ala33Leu34Gln35) in TβRI. Mutating the cilia-targeting signal abolished the trafficking of TβRI to the primary cilia. Localization of TβRI to primary cilia activated a key mediator of Shh signaling, Smoothened (Smo), which stimulated cellular migration and invasion. TβRI-Smo cross-talk at the cilia in CerS4-deficient 4T1 mammary cancer cells induced liver metastasis from orthotopic allografts in both wild-type and CerS4-deficient mice, which was prevented by overexpression of Smad7 or knockdown of intraflagellar transport protein 88 (IFT88). Overall, these data reveal a ceramide-dependent mechanism that suppresses cell migration and invasion by restricting TβRI/II-Shh signaling selectively at the plasma membrane of the primary cilium.

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Section: Discussionmentioning

confidence: 99%

TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis

et al. 2017

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“…Interestingly, in Gaucher disease, complement signalling via complement C5a and C5a receptor 1 (C5aR1) induced the accumulation of glucosylceramide and tissue inflammation 141 . Moreover, CERS6-generated C16 ceramide increased T cell response to alloantigens during allogeneic haematopoietic stem cell transplantation (allo-HSCT) in a mouse model of leukaemia, an effective immunotherapy for various haematological malignancies 142 . Interestingly, data revealed that genetic loss of CERS6 prevented development of graft-versus-host disease in mouse models, a major toxic effect limiting the anti-leukaemic efficacy of allo-HSCT 142 .…”

Section: Sphingolipids and Cancer Therapymentioning

confidence: 99%

“…Moreover, CERS6-generated C16 ceramide increased T cell response to alloantigens during allogeneic haematopoietic stem cell transplantation (allo-HSCT) in a mouse model of leukaemia, an effective immunotherapy for various haematological malignancies 142 . Interestingly, data revealed that genetic loss of CERS6 prevented development of graft-versus-host disease in mouse models, a major toxic effect limiting the anti-leukaemic efficacy of allo-HSCT 142 . In addition, α-galactosylceramide — a marine-sponge-derived antitumour agent composed of ceramide conjugated to galactose via an α-linkage — was shown to activate natural killer cells 143 .…”

Section: Sphingolipids and Cancer Therapymentioning

confidence: 99%

Sphingolipid metabolism in cancer signalling and therapy

2017

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Sphingolipids, including the two central bioactive lipids ceramide and sphingosine-1-phosphate (S1P), have opposing roles in regulating cancer cell death and survival, respectively, and there have been exciting developments in understanding how sphingolipid metabolism and signalling regulate these processes in response to anticancer therapy. Recent studies have provided mechanistic details of the roles of sphingolipids and their downstream targets in the regulation of tumour growth and response to chemotherapy, radiotherapy and/or immunotherapy using innovative molecular, genetic and pharmacological tools to target sphingolipid signalling nodes in cancer cells. For example, structure–function-based studies have provided innovative opportunities to develop mechanism-based anticancer therapeutic strategies to restore anti-proliferative ceramide signalling and/or inhibit pro-survival S1P–S1P receptor (S1PR) signalling. This Review summarizes how ceramide-induced cellular stress mediates cancer cell death through various mechanisms involving the induction of apoptosis, necroptosis and/or mitophagy. Moreover, the metabolism of ceramide for S1P biosynthesis, which is mediated by sphingosine kinase 1 and 2, and its role in influencing cancer cell growth, drug resistance and tumour metastasis through S1PR-dependent or receptor-independent signalling are highlighted. Finally, studies targeting enzymes involved in sphingolipid metabolism and/or signalling and their clinical implications for improving cancer therapeutics are also presented.

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“…Although Cer levels were higher in lymphoblasts than in naïve cells, which supports a role for Cer in T cell activation (Sofi et al, 2017), CCR5 deficiency further increased Cer levels specifically in lymphoblasts. The Cer increase in CCR5 -/lymphoblasts did not cause spontaneous apoptosis (Fig.…”

Section: Discussionmentioning

confidence: 59%

CCR5 deficiency impairs CD4⁺T cell memory responses and antigenic sensitivity through increased ceramide synthesis

Martín-Leal

Blanco

Casas

et al. 2020

Preprint

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In CD4 + T cells, CCR5 is not only a coreceptor for HIV-1 infection, but also contributes to their functional fitness. Here we show that by limiting GATA-1-induced transcription of specific ceramide synthases, CCR5 signaling reduces ceramide levels and thereby increases T cell antigen receptor (TCR) nanoclustering in antigen-experienced mouse and human CD4 + T cells.This activity is CCR5-specific and independent of CCR5 costimulatory activity. CCR5deficient mice showed reduced production of high affinity class-switched antibodies, but only after antigen rechallenge, which implies an impaired memory CD4 + T cell response. This study identifies a CCR5 function in the generation of CD4 + T cell memory responses, and establishes an antigen-independent mechanism that regulates TCR nanoclustering by altering specific lipid species.

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Ceramide synthesis regulates T cell activity and GVHD development

Cited by 53 publications

References 55 publications

TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis

TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis

Sphingolipid metabolism in cancer signalling and therapy

CCR5 deficiency impairs CD4⁺T cell memory responses and antigenic sensitivity through increased ceramide synthesis

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Ceramide synthesis regulates T cell activity and GVHD development

Cited by 53 publications

References 55 publications

TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis

TGF-β receptor I/II trafficking and signaling at primary cilia are inhibited by ceramide to attenuate cell migration and tumor metastasis

Sphingolipid metabolism in cancer signalling and therapy

CCR5 deficiency impairs CD4+T cell memory responses and antigenic sensitivity through increased ceramide synthesis

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CCR5 deficiency impairs CD4⁺T cell memory responses and antigenic sensitivity through increased ceramide synthesis