A peptidic inhibitor for PD-1 palmitoylation targets its expression and functions

Yao, Han; Li, Chushu; He, Fang; Song, Tianze; Brosseau, Jean-Philippe; Wang, Huanbin; Lu, Haojie; Fang, Changming; Shi, Hubing; Jiang, Lan; Fang, Jing‐Yuan; Xu, Jin-Quan

doi:10.1039/d0cb00157k

Cited by 37 publications

(31 citation statements)

References 26 publications

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“…PD-1 ligands PD-L1 and PD-L2 are expressed on antigen-presenting cells and tumour cells. In silico motif-based prediction identified PD-1 S -palmitoylation at Cys192 between its transmembrane and cytosolic domain, which was confirmed by metabolic labelling studies [ 56 ]. PD-1 S -palmitoylation is catalysed by DHHC9.…”

Section: S -Palmitoylation Of Proteins In Adaptive Immunitymentioning

confidence: 83%

Protein S -palmitoylation in immunity

2021

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S -palmitoylation is a reversible posttranslational lipid modification of proteins. It controls protein activity, stability, trafficking and protein–protein interactions. Recent global profiling of immune cells and targeted analysis have identified many S -palmitoylated immunity-associated proteins. Here, we review S -palmitoylated immune receptors and effectors, and their dynamic regulation at cellular membranes to generate specific and balanced immune responses. We also highlight how this understanding can drive therapeutic advances to pharmacologically modulate immune responses.

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Section: S -Palmitoylation Of Proteins In Adaptive Immunitymentioning

confidence: 83%

Protein S -palmitoylation in immunity

2021

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“…Yao et al . also found that PD-1 on the surface of tumor cells could be modified by zDHHC9-mediated palmitoylation, and inhibition of PD-1 palmitoylation significantly reduced the expression of PD-1 on the surface of tumor cells and inhibited tumor growth 39 . Therefore, inhibiting the palmitoylation of PD-1 on the surface of tumor cells and immune cells at the same time or combining with PD-1/PD-L1 inhibitors may be an effective treatment strategy.…”

Section: Protein Palmitoylation Regulates Pd-1/pd-l1 Signalingmentioning

confidence: 83%

Emerging roles of protein palmitoylation and its modifying enzymes in cancer cell signal transduction and cancer therapy

Liu¹,

Xiao²,

Mo³

et al. 2022

Int. J. Biol. Sci.

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Protein palmitoylation is an increasingly investigated form of post-translational lipid modification that affects protein localization, accumulation, secretion and function. Recently, emerging findings have revealed that protein palmitoylation is crucial for many tumor-related signaling pathways, such as EGFR, RAS, PD-1/PD-L1 signaling, affecting the occurrence, progression and therapeutic response of tumors. Protein palmitoylation and its modifying enzymes, including palmitoylases and depalmitoylases, are expected to be new targets for effective tumor treatment. Recognizing the significance of palmitoylation modification on protein stability, localization and downstream signal regulation, this review focuses on the regulatory roles of protein palmitoylation and its modifying enzymes in tumor cell signal transduction, aiming to bring new ideas for effective cancer prevention and treatment.

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“…We envision that a crystal structure of a PATi-bound DHHC would both aid in deciphering the mechanism of the cyanomethyl-mediated increase in potency and highlight opportunities for structure-based design. In addition, the capability of zDHHC20 to acylate NRas peptide, as well as recent reports of DHHC-targeted peptide inhibitors, hint at the potential of peptide scaffolds as DHHC inhibitors [48][49] . Our future work will focus on modifying small molecule and peptide scaffolds to achieve improvements in selectivity and potency.…”

Section: Discussionmentioning

confidence: 99%

Development of an Acrylamide-Based Inhibitor of Protein S-Acylation

Azizi¹,

Lan²,

Delalande³

et al. 2021

Preprint

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<div><div><div><p>Protein S-acylation is a dynamic lipid post-translational modification that can modulate the localization and activity of target proteins. In humans, the installation of the lipid onto target proteins is catalyzed by a family of 23 Asp-His-His-Cys domain-containing protein acyltransferases (DHHC-PATs). DHHCs are increasingly recognized as critical players in cellular signaling events and in human disease. However, progress elucidating the functions and mechanisms of DHHC “writers” has been hampered by a lack of chemical tools to perturb their activity in live cells. Herein, we report the synthesis and characterization of PATi, a pan- DHHC inhibitor more potent than 2-bromopalmitate (2BP), the most commonly used DHHC inhibitor in the field. Possessing an acrylamide warhead, PATi pairs its gain in potency with decreases in both toxicity and inhibition of the S-acylation eraser enzymes – two of the major weaknesses of 2BP. Our studies show that PATi engages with DHHC family proteins in cells, inhibits protein S-acylation, and disrupts DHHC-regulated cellular events. PATi represents an improved chemical tool for untangling the complexities of DHHC-mediated cell signaling by protein S-acylation.</p></div></div></div>

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A peptidic inhibitor for PD-1 palmitoylation targets its expression and functions

Cited by 37 publications

References 26 publications

Protein S -palmitoylation in immunity

Protein S -palmitoylation in immunity

Emerging roles of protein palmitoylation and its modifying enzymes in cancer cell signal transduction and cancer therapy

Development of an Acrylamide-Based Inhibitor of Protein S-Acylation

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