KLHL22 maintains PD-1 homeostasis and prevents excessive T cell suppression

Zhou, Xiao Albert; Zhou, Jiadong; Zhao, Long; Yu, Guihui; Zhan, Jun; Shi, Chanyi; Yuan, Ruoshi; Wang, Yan; Chen, Changfeng; Zhang, Wenjia; Xu, Donghao; Ye, Yingjiang; Wang, Weibin; Shen, Zhanlong; Wang, Wei; Wang, Jiadong

doi:10.1073/pnas.2004570117

Cited by 49 publications

(39 citation statements)

References 53 publications

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“…This discrepancy of PD-1 expression in cancer cells may reflect the unknown mechanisms by which the PD-1 was regulated by other layers including posttranscription, translation or even protein degradation. Actually, the proteasomal-dependent degradation of PD-1 in T cells has been recently reported ( 45 , 46 ). It is noteworthy to evaluate whether this regulation on PD-1 stability was also applied to cancer cell–intrinsic PD-1.…”

Section: Discussionmentioning

confidence: 99%

An unexpected role for p53 in regulating cancer cell–intrinsic PD-1 by acetylation

et al. 2021

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Cancer cell–intrinsic programmed cell death protein-1 (PD-1) has emerged as a tumor regulator in an immunity-independent manner, but its precise role in modulating tumor behaviors is complex, and how PD-1 is regulated in cancer cells is largely unknown. Here, we identified PD-1 as a direct target of tumor suppressor p53. Notably, p53 acetylation at K120/164 played a critical role in p53-mediated PD-1 transcription. Acetylated p53 preferentially recruited acetyltransferase cofactors onto PD-1 promoter, selectively facilitating PD-1 transcription by enhancing local chromatin acetylation. Reexpression of PD-1 in cancer cells inhibited tumor growth, whereas depletion of cancer cell–intrinsic PD-1 compromised p53-dependent tumor suppression. Moreover, histone deacetylase inhibitor (HDACi) activated PD-1 in an acetylated p53–dependent manner, supporting a synergistic effect by HDACi and p53 on tumor suppression via stimulating cancer cell–intrinsic PD-1. Our study reveals a mechanism for activating cancer cell–intrinsic PD-1 and indicates that p53-mediated PD-1 activation is critically involved in tumor suppression in an immunity-independent manner.

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Section: Discussionmentioning

confidence: 99%

An unexpected role for p53 in regulating cancer cell–intrinsic PD-1 by acetylation

et al. 2021

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“…As the receptor of PD-L1, PD-1 is also subjected to PTMs, including ubiquitination, glycosylation, and fucosylation [ 71 , 72 ]. PD-1 expression is regulated by E3 ligases F-box protein 38 (FBXO38) [ 73 ], c-Cbl [ 74 ], and the Kelch-like protein 22–Cullin-3–Ring-box 1 (KLHL22–CUL3–RBX1) complex [ 75 ], which mediate K48-linked polyubiquitination and subsequent proteasome degradation. The KLHL22–CUL3–RBX1 complex also mediates the ubiquitination of incompletely glycosylated PD-1 and degradation of PD-1 before its transportation to the cell surface [ 75 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

“…PD-1 expression is regulated by E3 ligases F-box protein 38 (FBXO38) [ 73 ], c-Cbl [ 74 ], and the Kelch-like protein 22–Cullin-3–Ring-box 1 (KLHL22–CUL3–RBX1) complex [ 75 ], which mediate K48-linked polyubiquitination and subsequent proteasome degradation. The KLHL22–CUL3–RBX1 complex also mediates the ubiquitination of incompletely glycosylated PD-1 and degradation of PD-1 before its transportation to the cell surface [ 75 ]. Fucosylation mediated by fucosyltransferase Fut8 at N49 and N74 regulates PD-1 cell surface expression.…”

Section: Future Perspectivesmentioning

confidence: 99%

Posttranslational Modifications in PD-L1 Turnover and Function: From Cradle to Grave

Young

et al. 2021

Biomedicines

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Programmed death-ligand 1 (PD-L1) is one of the most classic immune checkpoint molecules. Cancer cells express PD-L1 to inhibit the activity of effector T cells’ cytotoxicity through programmed death 1 (PD-1) engagement in exposure to inflammatory cytokines. PD-L1 expression levels on cancer cells might affect the clinical response to anti-PD-1/PD-L1 therapies. Hence, understanding molecular mechanisms for regulating PD-L1 expression is essential for improving the clinical response rate and efficacy of PD-1/PD-L1 blockade. Posttranslational modifications (PTMs), including phosphorylation, glycosylation, ubiquitination, and acetylation, regulate PD-L1 stability, cellular translocation, and interaction with its receptor. A coordinated positive and negative regulation via PTMs is required to ensure the balance and function of the PD-L1 protein. In this review, we primarily focus on the roles of PTMs in PD-L1 expression, trafficking, and antitumor immune response. We also discuss the implication of PTMs in anti-PD-1/PD-L1 therapies.

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“…FBXO38 is important for controlling the anti-tumor activity of T cells by regulating the expression of PD-1 [111,112]. The E3 ligase KLHL22 interacts with PD-1 and promotes the ubiquitination degradation of PD-1 before transportation to the cell surface, thereby enhancing tumor immunity [140].…”

Section: Regulation Of Immunitymentioning

confidence: 99%

E3 ubiquitin ligases: styles, structures and functions

et al. 2021

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E3 ubiquitin ligases are a large family of enzymes that join in a three-enzyme ubiquitination cascade together with ubiquitin activating enzyme E1 and ubiquitin conjugating enzyme E2. E3 ubiquitin ligases play an essential role in catalyzing the ubiquitination process and transferring ubiquitin protein to attach the lysine site of targeted substrates. Importantly, ubiquitination modification is involved in almost all life activities of eukaryotes. Thus, E3 ligases might be involved in regulating various biological processes and cellular responses to stress signal associated with cancer development. Thanks to their multi-functions, E3 ligases can be a promising target of cancer therapy. A deeper understanding of the regulatory mechanisms of E3 ligases in tumorigenesis will help to find new prognostic markers and accelerate the growth of anticancer therapeutic approaches. In general, we mainly introduce the classifications of E3 ligases and their important roles in cancer progression and therapeutic functions.

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KLHL22 maintains PD-1 homeostasis and prevents excessive T cell suppression

Cited by 49 publications

References 53 publications

An unexpected role for p53 in regulating cancer cell–intrinsic PD-1 by acetylation

An unexpected role for p53 in regulating cancer cell–intrinsic PD-1 by acetylation

Posttranslational Modifications in PD-L1 Turnover and Function: From Cradle to Grave

E3 ubiquitin ligases: styles, structures and functions

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