Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2

Wu, Zhen; Cao, Zhijie; Yao, Han; Xu, Wenbin; Zhang, Mi; Jiao, Zishan; Zhang, Zijing; Chen, Jianyuan; Liu, Yajing; Zhang, Meng

doi:10.1016/j.celrep.2023.112693

Cited by 9 publications

(2 citation statements)

References 59 publications

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“…Recently, Wu et al demonstrated that ubiquitination and breakdown of PD-1 require elimination of N-linked glycosylation and identified MDM2 as an E3 ligase for deglycosylation of PD-1. These enzymes facilitate the interaction between glycosylated PD-1 and N-glycanase 1 (NGLY1), leading to further deglycosylation of PD-1 catalyzed by NGLY1 [ 138 ]. These preclinical studies suggest that the ubiquitination of PD-1 is expected to become a new focus in the development of anticancer medications [ 139 ].…”

Section: Preclinical Study Of Ptms Regulating Pd-1 Expression and Fun...mentioning

confidence: 99%

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

Wang,

He,

Long

et al. 2024

Exp Hematol Oncol

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The interaction between programmed cell death ligand 1 (PD-L1), which is expressed on the surface of tumor cells, and programmed cell death 1 (PD-1), which is expressed on T cells, impedes the effective activation of tumor antigen-specific T cells, resulting in the evasion of tumor cells from immune-mediated killing. Blocking the PD-1/PD-L1 signaling pathway has been shown to be effective in preventing tumor immune evasion. PD-1/PD-L1 blocking antibodies have garnered significant attention in recent years within the field of tumor treatments, given the aforementioned mechanism. Furthermore, clinical research has substantiated the efficacy and safety of this immunotherapy across various tumors, offering renewed optimism for patients. However, challenges persist in anti-PD-1/PD-L1 therapies, marked by limited indications and the emergence of drug resistance. Consequently, identifying additional regulatory pathways and molecules associated with PD-1/PD-L1 and implementing judicious combined treatments are imperative for addressing the intricacies of tumor immune mechanisms. This review briefly outlines the structure of the PD-1/PD-L1 molecule, emphasizing the posttranslational modification regulatory mechanisms and related targets. Additionally, a comprehensive overview on the clinical research landscape concerning PD-1/PD-L1 post-translational modifications combined with PD-1/PD-L1 blocking antibodies to enhance outcomes for a broader spectrum of patients is presented based on foundational research.

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Section: Preclinical Study Of Ptms Regulating Pd-1 Expression and Fun...mentioning

confidence: 99%

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

Wang,

He,

Long

et al. 2024

Exp Hematol Oncol

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“…ISG15 influenced glycosylated PD-L1 and induced its destruction to increase antitumor immune functions in lung adenocarcinoma ( 129 ). MDM2 (murine double minute 2) governed degradation of PD-1 through regulating crosstalk between ubiquitination and deglycosylation in tumor cells ( 130 ). Removal of N-glycosylation increased the detection of PD-L1 and provided the prediction of anti-PD-1/PD-L1 treatment efficacy ( 139 ).…”

Section: Pd-1 and Pd-l1 Are Regulated By Ptmsmentioning

confidence: 99%

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Ren,

Wang,

Liu

et al. 2024

Front. Immunol.

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Immunotherapy has been developed, which harnesses and enhances the innate powers of the immune system to fight disease, particularly cancer. PD-1 (programmed death-1) and PD-L1 (programmed death ligand-1) are key components in the regulation of the immune system, particularly in the context of cancer immunotherapy. PD-1 and PD-L1 are regulated by PTMs, including phosphorylation, ubiquitination, deubiquitination, acetylation, palmitoylation and glycosylation. PROTACs (Proteolysis Targeting Chimeras) are a type of new drug design technology. They are specifically engineered molecules that target specific proteins within a cell for degradation. PROTACs have been designed and demonstrated their inhibitory activity against the PD-1/PD-L1 pathway, and showed their ability to degrade PD-1/PD-L1 proteins. In this review, we describe how PROTACs target PD-1 and PD-L1 proteins to improve the efficacy of immunotherapy. PROTACs could be a novel strategy to combine with radiotherapy, chemotherapy and immunotherapy for cancer patients.

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Doxorubicin induces deglycosylation of cancer cell‐intrinsic PD‐1 by NGLY1

Wu,

Yao

et al. 2024

FEBS Letters

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Tumor cells can express the immune checkpoint protein programmed death‐1 (PD‐1), but how cancer cell‐intrinsic PD‐1 is regulated in response to cellular stresses remains largely unknown. Here, we uncover a unique mechanism by which the chemotherapy drug doxorubicin (Dox) regulates cancer cell‐intrinsic PD‐1. Dox upregulates PD‐1 mRNA while reducing PD‐1 protein levels in tumor cells. Although Dox shortens the PD‐1 half‐life, it fails to directly induce PD‐1 degradation. Instead, we observe that Dox promotes the interaction between peptide‐N(4)‐(N‐acetyl‐beta‐glucosaminyl)asparagine amidase (NGLY1) and PD‐1, facilitating NGLY1‐mediated PD‐1 deglycosylation and destabilization. The maintenance of PD‐1 sensitizes tumor cells to Dox‐mediated antiproliferative effects. Our study unveils a regulatory mechanism of PD‐1 in response to Dox and highlights a potential role of cancer cell‐intrinsic PD‐1 in Dox‐mediated antitumor effects.

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Coupled deglycosylation-ubiquitination cascade in regulating PD-1 degradation by MDM2

Cited by 9 publications

References 59 publications

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

Emerging therapeutic frontiers in cancer: insights into posttranslational modifications of PD-1/PD-L1 and regulatory pathways

PTMs of PD-1/PD-L1 and PROTACs application for improving cancer immunotherapy

Doxorubicin induces deglycosylation of cancer cell‐intrinsic PD‐1 by NGLY1

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