FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells

Meng, Xiangbo; Liu, Xiwei; Guo, Xingdong; Jiang, Shanwen; Chen, Tingting; Hu, Zhiqiang; Liu, Haifeng; Bai, Yalai; Xue, Manman; Hu, Ronggui; Sun, Shao Cong; Liu, Xiaolong; Zhou, Penghui; Huang, Xiaowu; Wei, Lai; Yang, Wei; Xu, Chenqi

doi:10.1038/s41586-018-0756-0

Cited by 197 publications

(185 citation statements)

References 30 publications

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“…500 FBXO38, an E3 ligase of PD-1, mediates K48-linked polyubiquitination and subsequent proteasome degradation in activated T cells. 501 Additionally, COP9 signalosome 5 (CSN5) is required for PD-L1 stabilization by inhibiting its ubiquitination and degradation in cancer cells. 502 However, the specific role of ubiquitination in T cells, macrophages and DC cells is still unclear, especially for immunotherapies targeting ubiquitination, and need further development.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

424

308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

424

308

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“…to either BTLA or PD-1. We used the GST-tagged, prephosphorylated tail of either PD-1 or BTLA to capture proteins from Jurkat lysates and defined their interactomes using mass spectrometry (MS; Meng et al, 2018;Peled et al, 2018). One-sided volcano plots revealed that PD-1 and BTLA both pulled down SHP1 and SHP2.…”

Section: Pd-1 Recruits Shp2 But Not Shp1 Whereas Btla Recruits Both mentioning

confidence: 99%

PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2

Hou

Fulzele

et al. 2020

Journal of Cell Biology

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Blockade antibodies of the immunoinhibitory receptor PD-1 can stimulate the anti-tumor activity of T cells, but clinical benefit is limited to a fraction of patients. Evidence suggests that BTLA, a receptor structurally related to PD-1, may contribute to resistance to PD-1 targeted therapy, but how BTLA and PD-1 differ in their mechanisms is debated. Here, we compared the abilities of BTLA and PD-1 to recruit effector molecules and to regulate T cell signaling. While PD-1 selectively recruited SHP2 over the stronger phosphatase SHP1, BTLA preferentially recruited SHP1 to more efficiently suppress T cell signaling. Contrary to the dominant view that PD-1 and BTLA signal exclusively through SHP1/2, we found that in SHP1/2 double-deficient primary T cells, PD-1 and BTLA still potently inhibited cell proliferation and cytokine production, albeit more transiently than in wild type T cells. Thus, PD-1 and BTLA can suppress T cell signaling through a mechanism independent of both SHP1 and SHP2.

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“…Dysfunctional T cells in the tumor microenvironment have an abnormally high expression of PD-1, and antibody inhibitors against PD-1 or its ligand (PD-L1) have become commonly used drugs to treat various types of cancer. A study showed that surface PD-1 undergoes internalization, subsequent ubiquitination and proteasome degradation in activated T cells [16].…”

Section: Introductionmentioning

confidence: 99%

Aging immune system-related blood cell DNA methylation can predict the onset of early stage colorectal cancer

Yuan

Liang

et al. 2020

Preprint

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Objective: There is a body of evidence that the aging immune system is linked to cancer.Here, we hypothesized that ubiquitination might play a key gatekeeper role in immune system aging and tumorigenesis in CRC. Therefore, we will systematically study the DNA methylation of ubiquitination genes and screen candidate CRC marker that are correlated with both aging and immune cell compositions.Design: Through aging-and immune-related DNA methylation data, we investigated the DNA methylation regulation changes in promoters with other regions of genes during aging and their association with the immune cell proportion in the circulating whole blood of healthy individuals. Then, by collecting a cohort of 100 colon cancer patients and 50 healthy individuals, we used nucleic acid mass spectrometry to test whether ubiquitination genes can be used as candidate markers for the early screening of CRC. Results:The biological analyses for aging-and CD4 T cell proportion-derived differential genes showed that they are associated with ubiquitination. Among them, DZIP3 was significantly associated with both aging (P-value = 3.86E-06) and CD4 T cell proportion (P-value = 1.97E-05) in circulating blood. Then, we validated that the 1 st exon DNA methylation of DZIP3 could predict the onset of early stage CRC (AUC = 0.833, OR = 8.82) and all pTNM stages of CRC (AUC = 0.782, OR = 5.70). Conclusions:The epigenetically regulated ubiquitination plays an important role in immune aging and tumorigenesis. DNA methylation characteristic of DZIP3 can be used as a promising marker of CRC early screening.

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FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells

Cited by 197 publications

References 30 publications

The role of ubiquitination in tumorigenesis and targeted drug discovery

The role of ubiquitination in tumorigenesis and targeted drug discovery

PD-1 and BTLA regulate T cell signaling differentially and only partially through SHP1 and SHP2

Aging immune system-related blood cell DNA methylation can predict the onset of early stage colorectal cancer

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