Caspase‐dependent cleavage regulates protein levels of Epstein–Barr virus‐derived latent membrane protein 1

Togi, Sumihito; Hatano, Yosuke; Muromoto, Ryuta; Kawanishi, Eri; Ikeda, Osamu; Hirashima, Koki; Kawa, Shigeyuki; Kitai, Yuichi; Yasui, Takeshi; Oritani, Kenji; Matsuda, Tadashi

doi:10.1002/1873-3468.12119

Cited by 4 publications

(5 citation statements)

References 37 publications

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“…Finally, considering the association of EBV infection in the biology of NPC, the involvement of viral proteins such as latent membrane protein1 (LMP1) in the induction and/or membrane recruitment of pro-caspase-3 can also not be ruled out. In this regard, not only caspase-3 was shown to proteolytically cleave LMP1, but more importantly, LMP1 expression was reported to induce the expression of caspase-3 [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3

et al. 2021

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Aims Preferential expression of receptors for TNF-family related apoptosis inducing ligand (TRAIL), DR4 and DR5 makes TRAIL an attractive anti-cancer therapeutic. However, the efficacy of targeting death receptors has not been extensively studied in nasopharyngeal cancer (NPC). Here we investigated TRAIL sensitivity and its underlying mechanism in NPC cell lines, and assessed the potential of TRAIL as a therapeutic option against NPC. Results Using two established NPC cell lines, we report the expression of DR4 and DR5, which respond to TRAIL ligation by triggering efficient Type II apoptosis. Mechanistically, early activation of caspase-3 and its membrane recruitment is identified in NPC cell lines, which is associated with, hitherto unreported, interaction with transmembrane and tetratricopeptide repeat containing 2 (TMTC2) in the lipid raft domains. TMTC2 expression is induced upon exposure to TRAIL and involves intracellular increase in peroxynitrite (ONOO − ) production. While ONOO − increase is downstream of caspase-8 activation, it is involved in the upregulation of TMTC2, gene knockdown of which abrogated TRAIL-induced apoptotic execution. Bioinformatics analyses also provide evidence for a strong correlation between TMTC2 and DR4 or caspase-3 as well as a significantly better disease-free survival in patients with high TMTC2 expression. Innovation and conclusion Collectively, redox-dependent execution of NPC cells upon ligation of TRAIL receptors reintroduces the possible therapeutic use of TRAIL in NPC as well as underscores the potential of using TMTC2 as a biomarker of TRAIL sensitivity.

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Section: Discussionmentioning

confidence: 99%

TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3

et al. 2021

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“…In addition, the cleavage of other cellular [ 56 , 91 , 92 , 93 , 94 ] or potentially viral proteins by caspase-1 and other caspases could also contribute to EBV reactivation. In addition to caspase cleavage of BPLF1, caspase-3 was reported cleave LMP1 in Hela cells while the functional importance is not clear [ 95 ]. Using bioinformatic tools PeptideCutter and GraBCas [ 96 , 97 ], we also predicted the potential caspase cleavage sites for EBV proteins and found that many other viral proteins, such as BCRF1/vIL10, may also be potentially cleaved by caspases ( S2 Table ).…”

Section: Discussionmentioning

confidence: 99%

Interferon regulatory factor 8 regulates caspase-1 expression to facilitate Epstein-Barr virus reactivation in response to B cell receptor stimulation and chemical induction

Zhang

2018

PLoS Pathog

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Interferon regulatory factor 8 (IRF8), also known as interferon consensus sequence-binding protein (ICSBP), is a transcription factor of the IRF family. IRF8 plays a key role in normal B cell differentiation, a cellular process that is intrinsically associated with Epstein-Barr virus (EBV) reactivation. However, whether IRF8 regulates EBV lytic replication remains unknown. In this study, we utilized a CRISPR/Cas9 genomic editing approach to deplete IRF8 and found that IRF8 depletion dramatically inhibits the reactivation of EBV upon lytic induction. We demonstrated that IRF8 depletion suppresses the expression of a group of genes involved in apoptosis and thus inhibits apoptosis induction upon lytic induction by B cell receptor (BCR) stimulation or chemical induction. The protein levels of caspase-1, caspase-3 and caspase-8 all dramatically decreased in IRF8-depleted cells, which led to reduced caspase activation and the stabilization of KAP1, PAX5 and DNMT3A upon BCR stimulation. Interestingly, caspase inhibition blocked the degradation of KAP1, PAX5 and DNMT3A, suppressed EBV lytic gene expression and viral DNA replication upon lytic induction, suggesting that the reduced caspase expression in IRF8-depleted cells contributes to the suppression of EBV lytic replication. We further demonstrated that IRF8 directly regulates CASP1 (caspase-1) gene expression through targeting its gene promoter and knockdown of caspase-1 abrogates EBV reactivation upon lytic induction, partially through the stabilization of KAP1. Together our study suggested that, by modulating the activation of caspases and the subsequent cleavage of KAP1 upon lytic induction, IRF8 plays a critical role in EBV lytic reactivation.

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“…Specifically, the median survival for patients with no expression of JAK2 or STAT3 was 58.7 ± 5.3 or 53.6 ± 13.1 months, while those with positive expression of JAK2 or STAT3 had median survival times of 33.6 ± 19.7 or 39.5 ± 20.8 months, respectively [ 274 , 275 ]. In NPC, this pathway is constitutively activated by LMP1 through CTAR3 activation and upregulation of IL-6 [ 276 – 278 ]. In fact, STAT is activated in a positive feedback loop manner, whereby STAT activation signalling upregulates the expression of LMP1, in turn induces the LMP1-mediated IL-6 production and results in activation of STAT [ 277 ].…”

Section: Molecular Aberrations Exploitation In Npc For Precision Medi...mentioning

confidence: 99%

“…In NPC, this pathway is constitutively activated by LMP1 through CTAR3 activation and upregulation of IL-6 [ 276 – 278 ]. In fact, STAT is activated in a positive feedback loop manner, whereby STAT activation signalling upregulates the expression of LMP1, in turn induces the LMP1-mediated IL-6 production and results in activation of STAT [ 277 ].…”

Section: Molecular Aberrations Exploitation In Npc For Precision Medi...mentioning

confidence: 99%

Precision medicine in nasopharyngeal carcinoma: comprehensive review of past, present, and future prospect

Siak,

Heng,

Teoh

et al. 2023

J Transl Med

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Nasopharyngeal carcinoma (NPC) is an aggressive malignancy with high propensity for lymphatic spread and distant metastasis. It is prominent as an endemic malignancy in Southern China and Southeast Asia regions. Studies on NPC pathogenesis mechanism in the past decades such as through Epstein Barr Virus (EBV) infection and oncogenic molecular aberrations have explored several potential targets for therapy and diagnosis. The EBV infection introduces oncoviral proteins that consequently hyperactivate many promitotic pathways and block cell-death inducers. EBV infection is so prevalent in NPC patients such that EBV serological tests were used to diagnose and screen NPC patients. On the other hand, as the downstream effectors of oncogenic mechanisms, the promitotic pathways can potentially be exploited therapeutically. With the apparent heterogeneity and distinct molecular aberrations of NPC tumor, the focus has turned into a more personalized treatment in NPC. Herein in this comprehensive review, we depict the current status of screening, diagnosis, treatment, and prevention in NPC. Subsequently, based on the limitations on those aspects, we look at their potential improvements in moving towards the path of precision medicine. The importance of recent advances on the key molecular aberration involved in pathogenesis of NPC for precision medicine progression has also been reported in the present review. Besides, the challenge and future outlook of NPC management will also be highlighted.

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Caspase‐dependent cleavage regulates protein levels of Epstein–Barr virus‐derived latent membrane protein 1

Cited by 4 publications

References 37 publications

TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3

TRAIL sensitivity of nasopharyngeal cancer cells involves redox dependent upregulation of TMTC2 and its interaction with membrane caspase-3

Interferon regulatory factor 8 regulates caspase-1 expression to facilitate Epstein-Barr virus reactivation in response to B cell receptor stimulation and chemical induction

Precision medicine in nasopharyngeal carcinoma: comprehensive review of past, present, and future prospect

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