A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation

Voigt, Stefanie; Sterz, Kai R.; Giehler, Fabian; Mohr, Anne-Wiebe; Wilson, Joanna B.; Moosmann, Andreas; Kieser, Arnd

doi:10.1038/s41467-020-14502-x

Cited by 17 publications

(28 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TPL2 is then phosphorylated and activated. Activated TPL2 activates nodal proteins via downstream signaling pathways to perform biological functions (20)(21)(22)(23). Recent studies have shown that TPL2 is also an important host immunoregulatory protein involved in innate and adaptive immunity, and it can resist the invasion of foreign pathogens.…”

Section: Introductionmentioning

confidence: 99%

Foot-and-Mouth Disease Virus Structural Protein VP1 Destroys the Stability of the TPL2 Trimer by Degradation of TPL2 To Evade Host Antiviral Immunity

Zhang

Yan

Hao

et al. 2021

J Virol

View full text Add to dashboard Cite

Tumor progression locus 2 (TPL2) is a serine/threonine kinase that belongs to the mitogen-activated protein 3 kinase (MAP3K) family, and it plays an important role in pathogen infection. The trimer complex of TPL2, p105, and ABIN2 is essential for maintenance of TPL2 steady-state levels and host cell response to pathogens. Foot-and-mouth disease virus (FMDV) is a positive-strand RNA virus of the family Picornaviridae that encodes proteins capable of antagonizing host immune responses to achieve infection. The VP1 protein of FMDV is a multifunctional protein that can bind host cells and induce an immune response as well as cell apoptosis. However, the role and mechanisms of TPL2 in FMDV infection remain unknown. Here, we determined that FMDV infection could inhibit TPL2, p105, and ABIN2 at the transcription and protein levels, while VP1 could only inhibit TPL2, p105 and ABIN2 at protein level. TPL2 inhibited the replication of FMDV in vivo and in vitro, the 268 to 283 amino-acid region in the TPL2 kinase domain was essential for interaction with VP1. Moreover, VP1 promoted K48-linked polyubiquitination of TPL2 and degraded TPL2 by the proteasome pathway. However, VP1-induced degradation of p105 and ABIN2 was independent of proteasome, autophagy, lysosome, and caspase-dependent pathways. Further studies showed that VP1 destroyed the stability of the TPL2-p105-ABIN2 complex. Taken together, these results revealed that VP1 antagonized TPL2-meditated antivirus activity by degrading TPL2 and destroying its complex. These findings may contribute to understand FMDV-host interactions and improve development of a novel vaccine to prevent FMDV infection. Importance Virus-host interactions are critical for virus infection. This study was the first to demonstrate the antiviral effect of host TPL2 during FMDV replication by increasing production of interferons and antiviral cytokines. Both FMDV and VP1 protein can reduce host TPL2, ABIN2 and p105 to destroy TPL2-p105-ABIN2 trimer complex. VP1 interacted with TPL2 and degrade TPL2 via proteasome pathway to repress TPL2-mediated antivirus activity. This study provided new insights into FMDV immune evasion mechanisms, elucidating new informations regarding FMDV counteraction of host antivirus activity.

show abstract

Section: Introductionmentioning

confidence: 99%

Foot-and-Mouth Disease Virus Structural Protein VP1 Destroys the Stability of the TPL2 Trimer by Degradation of TPL2 To Evade Host Antiviral Immunity

Zhang

Yan

Hao

et al. 2021

J Virol

View full text Add to dashboard Cite

show abstract

“…They also discovered that an ethanol extract of Chrysanthemum indicum Linné (CIE) can strikingly reduce LMP1-induced NF-κB activation as well as LCL activity but produces no negative effects on human foreskin fibroblasts (HFFs), EBV-negative Burkitt lymphoma cells or HeLa cells. Further evidence suggests that the LMP1-induced IKK2-TPL2 signaling pathway may mediate JNK signaling to effectively regulate the proliferation and survival of EBV-transformed LCLs [ 18 ]. LMP1 can also regulate cell migration and invasion abilities through NF-κB.…”

Section: Six Main Signaling Pathways Of Ebv-associated Neoplasmsmentioning

confidence: 99%

Signaling pathways of EBV-induced oncogenesis

et al. 2021

View full text Add to dashboard Cite

Epstein-Barr virus (EBV) is closely associated with multiple human cancers. EBV-associated cancers are mainly lymphomas derived from B cells and T cells (Hodgkin lymphoma, Burkitt lymphoma, NK/T-cell lymphoma, and posttransplant lymphoproliferative disorder (PTLD)) and carcinomas derived from epithelial cells (nasopharyngeal carcinoma and gastric carcinoma). EBV can induce oncogenesis in its host cell by activating various signaling pathways, such as nuclear factor-κB (NF-κB), phosphoinositide-3-kinase/protein kinase B (PI3K/AKT), Janus kinase/signal transducer and transcription activator (JAK/STAT), mitogen-activated protein kinase (MAPK), transforming growth factor-β (TGF-β), and Wnt/β-catenin, which are regulated by EBV-encoded proteins and noncoding RNA. In this review, we focus on the oncogenic roles of EBV that are mediated through the aforementioned signaling pathways.

show abstract

“…TPL2 signaling is also directly implicated in viral-induced malignant transformation and tumor progression. For example, the oncogenic Epstein-Barr virus (EBV), linked to Hodgkin's lymphoma and EBV-associated nasopharyngeal carcinoma, is shown to activate the TPL2 kinase, which then modulates viral lytic replication, NF-κB and AP-1 activation, inflammation and tumor progression 24 , 25 . The identified role of TPL2 signaling as a target and modulator of pathogen-driven tumorigenesis needs further investigation.…”

Section: Tpl2 and Tumor-promoting Inflammationmentioning

confidence: 99%

“…The tumor microenvironment in mature tumors is characterized by a heterogeneous group of activated fibroblasts known as cancer-associated fibroblasts (CAFs) that interact with cancer cells and other stromal cells to propagate tumor growth and disease progression 44 , 87 . The TPL2 activity is implicated in CAFs activation, where it sustains the pro-inflammatory transcriptional signature that contributes to tumor progression and metastasis 25 , 65 . Despite its essential role in the production of inflammatory factors, TPL2 loss in CAFs was reported to promote NF-κB activation, inflammation and tumorigenesis 88 .…”

Section: Tpl2 and Tumor Immunitymentioning

confidence: 99%

Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

Njunge¹,

Estania²,

Guo³

et al. 2020

Theranostics

View full text Add to dashboard Cite

Over the years, tumor progression locus 2 (TPL2) has been identified as an essential modulator of immune responses that conveys inflammatory signals to downstream effectors, subsequently modulating the generation and function of inflammatory cells. TPL2 is also differentially expressed and activated in several cancers, where it is associated with increased inflammation, malignant transformation, angiogenesis, metastasis, poor prognosis and therapy resistance. However, the relationship between TPL2-driven inflammation, tumorigenesis and tumor immunity has not been addressed. Here, we reconcile the function of TPL2-driven inflammation to oncogenic functions such as inflammation, proliferation, apoptosis resistance, angiogenesis, metastasis, immunosuppression and immune evasion. We also address the controversies reported on TPL2 function in tumor-promoting inflammation and tumorigenesis, and highlight the potential role of the TPL2 adaptor function in regulating the mechanisms leading to pro-tumorigenic inflammation and tumor progression. We discuss the therapeutic implications and limitations of targeting TPL2 for cancer treatment. The ideas presented here provide some new insight into cancer pathophysiology that might contribute to the development of more integrative and specific anti-inflammatory and anti-cancer therapeutics.

show abstract

A central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation

Cited by 17 publications

References 70 publications

Foot-and-Mouth Disease Virus Structural Protein VP1 Destroys the Stability of the TPL2 Trimer by Degradation of TPL2 To Evade Host Antiviral Immunity

Foot-and-Mouth Disease Virus Structural Protein VP1 Destroys the Stability of the TPL2 Trimer by Degradation of TPL2 To Evade Host Antiviral Immunity

Signaling pathways of EBV-induced oncogenesis

Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

Contact Info

Product

Resources

About