The p38‐interacting protein p38IP suppresses TCR and LPS signaling by targeting TAK1

Wang, Xiaojia; Zhao, Chen-si; Wang, Qilong; Zeng, Qi; Feng, Xingzhi; Li, Lianbo; Chen, Zhilong; Gong, Yu; Han, Jiahuai; Li, Yingqiu

doi:10.15252/embr.201948035

Cited by 9 publications

(5 citation statements)

References 71 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A previous study identified the role of SP20H as a negative regulator controlling T cell receptor and LPS-activated NF-κB and p38 signaling in Jurkat T cells. 46 In line with this, activation of the TNF-p38 MAPK pathway is found in SP20H -knockout tumor cells, which is responsible for further induction of B7-H3 expression. Perhaps even more importantly, human eukaryotic translation initiation factor 4E (eIF4E), which interacts with eIF4A and eIF4G to assemble an active eIF4F complex that assumes cap-dependent translation, was characterized as a positive regulator of B7-H3 expression in our study.…”

Section: Discussionmentioning

confidence: 70%

Genome-scale CRISPR–Cas9 screen reveals novel regulators of B7-H3 in tumor cells

Zhao

Wang

Yang

et al. 2022

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundDespite advances in B7 homolog 3 protein (B7-H3) based immunotherapy, the development of drug resistance remains a major clinical concern. The heterogeneity and emerging loss of B7-H3 expression are the main causes of drug resistance and treatment failure in targeted therapies, which reveals an urgent need to elucidate the mechanism underlying the regulation of B7-H3 expression. In this study, we identified and explored the crucial role of the transcription factor SPT20 homolog (SP20H) in B7-H3 expression and tumor progression.MethodsHere, we performed CRISPR/Cas9-based genome scale loss-of-function screening to identify regulators of B7-H3 in human ovarian cancer cells. Signaling pathways altered by SP20H knockout were revealed by RNA sequencing. The regulatory role and mechanism of SP20H in B7-H3 expression were validated using loss-of-function and gain-of-function assays in vitro. The effects of inhibiting SP20H on tumor growth and efficacy of anti-B7-H3 treatment were evaluated in tumor-bearing mice.ResultsWe identified SUPT20H (SP20H) as negative and eIF4E as positive regulators of B7-H3 expression in various cancer cells. Furthermore, we provided evidence that either SP20H loss or TNF-α stimulation in tumor cells constitutively activates p38 MAPK-eIF4E signaling, thereby upregulating B7-H3 expression. Loss of SP20H upregulated B7-H3 expression both in vitro and in vivo. Additionally, deletion of SP20H significantly suppressed tumor growth and increased immune cells infiltration in tumor microenvironment. More importantly, antibody–drug conjugates targeting B7-H3 exhibited superior antitumor performance against SP20H-deficient tumors relative to control groups.ConclusionsActivation of p38 MAPK-eIF4E signaling serves as a key event in the transcription initiation and B7-H3 protein expression in tumor cells. Genetically targeting SP20H upregulates target antigen expression and sensitizes tumors to anti-B7-H3 treatment. Collectively, our findings provide new insight into the mechanisms underlying B7-H3 expression and introduce a potential synergistic target for existing antibody-based targeted therapy against B7-H3.

show abstract

Section: Discussionmentioning

confidence: 70%

Genome-scale CRISPR–Cas9 screen reveals novel regulators of B7-H3 in tumor cells

Zhao

Wang

Yang

et al. 2022

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…Being responsible for the various distinct and even opposing fundamental cellular processes, the p38 cascade needs to be tightly regulated. Indeed, several regulatory mechanisms that determine the specificity of the cascade have been identified, including the duration and strength of the signals [ 13 , 14 ], which are controlled mainly by dual specificity phosphatases [ 15 , 16 ], scaffold proteins [ 17 ], and dynamic subcellular localization of the cascade’s components [ 18 ]. Importantly, the central roles of the cascade suggest that its dysregulation may cause various diseases.…”

Section: Introductionmentioning

confidence: 99%

Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

Maik-Rachline

Lifshits

Seger

2020

IJMS

View full text Add to dashboard Cite

The p38 mitogen-activated protein kinase (p38MAPK, termed here p38) cascade is a central signaling pathway that transmits stress and other signals to various intracellular targets in the cytoplasm and nucleus. More than 150 substrates of p38α/β have been identified, and this number is likely to increase. The phosphorylation of these substrates initiates or regulates a large number of cellular processes including transcription, translation, RNA processing and cell cycle progression, as well as degradation and the nuclear translocation of various proteins. Being such a central signaling cascade, its dysregulation is associated with many pathologies, particularly inflammation and cancer. One of the hallmarks of p38α/β signaling is its stimulated nuclear translocation, which occurs shortly after extracellular stimulation. Although p38α/β do not contain nuclear localization or nuclear export signals, they rapidly and robustly translocate to the nucleus, and they are exported back to the cytoplasm within minutes to hours. Here, we describe the physiological and pathological roles of p38α/β phosphorylation, concentrating mainly on the ill-reviewed regulation of p38α/β substrate degradation and nuclear translocation. In addition, we provide information on the p38α/β ′s substrates, concentrating mainly on the nuclear targets and their role in p38α/b functions. Finally, we also provide information on the mechanisms of nuclear p38α/b translocation and its use as a therapeutic target for p38α/β-dependent diseases.

show abstract

“…Mechanistically, p38IP dynamically interacts with TAK1 and promotes USP4-dependent deubiquitination of TAK1. Moreover, p38IP also inhibits the unanchored K63-linked ubiquitin chains binding to TAK1 (114). TAK1 activity can also be terminated by deubiquitinase cylindromatosis (Cyld) and E3 ubiquitin ligase Itch complex.…”

Section: Ubiquitination-mediated Regulation Of Tak1-tabs Signalosomementioning

confidence: 99%

TAK1-TABs Complex: A Central Signalosome in Inflammatory Responses

Lei

2021

Front. Immunol.

123

View full text Add to dashboard Cite

Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is a member of the MAPK kinase kinase (MAPKKK) family and has been implicated in the regulation of a wide range of physiological and pathological processes. TAK1 functions through assembling with its binding partners TAK1-binding proteins (TAB1, TAB2, and TAB3) and can be activated by a variety of stimuli such as tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and toll-like receptor ligands, and they play essential roles in the activation of NF-κB and MAPKs. Numerous studies have demonstrated that post-translational modifications play important roles in properly controlling the activity, stability, and assembly of TAK1-TABs complex according to the indicated cellular environment. This review focuses on the recent advances in TAK1-TABs-mediated signaling and the regulations of TAK1-TABs complex by post-translational modifications.

show abstract

The p38‐interacting protein p38IP suppresses TCR and LPS signaling by targeting TAK1

Cited by 9 publications

References 71 publications

Genome-scale CRISPR–Cas9 screen reveals novel regulators of B7-H3 in tumor cells

Genome-scale CRISPR–Cas9 screen reveals novel regulators of B7-H3 in tumor cells

Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

TAK1-TABs Complex: A Central Signalosome in Inflammatory Responses

Contact Info

Product

Resources

About