Palmitoylation restricts SQSTM1/p62-mediated autophagic degradation of NOD2 to modulate inflammation

Zhou, Lingli; He, Xing; Wang, Liqiu; Wei, Ping; Cai, Zhe; Zhang, Song; Zeng, Huasong; Cui, Jun

doi:10.1038/s41418-022-00942-z

Cited by 28 publications

(14 citation statements)

References 38 publications

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“…Palmitoylation of proteins was analyzed using acyl-biotin exchange (ABE) assays as previously described, with some modifications ( 49 , 50 ). SUNE-1 cells treated with MGH-CP1 (S9735, Selleck) or transiently expressing Myc-tagged wild-type or palmitoylation-deficient (C335S, C367A) TEAD4 were subjected to ABE assay.…”

Section: Methodsmentioning

confidence: 99%

TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma

Wang

Wei

et al. 2023

Sci. Adv.

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The molecular basis underlying nasopharyngeal carcinoma (NPC) remains unclear. Recent progress in transcriptional regulatory network analysis helps identify the master regulator (MR) proteins that transcriptionally define malignant tumor phenotypes. Here, we investigated transcription factor-target interactions and identified TEA domain transcription factor 4 (TEAD4) as an MR of high-risk NPC. Precisely, TEAD4 promoted NPC migration, invasion and cisplatin resistance, depending on its autopalmitoylation. Mechanistically, YTHDF2 (YTH domain family 2) recognized WTAP (Wilms tumor 1–associating protein)–mediated TEAD4 m 6 A methylation to facilitate its stability and led to aberrant up-regulation of TEAD4. Up-regulated TEAD4 further drove NPC progression by transcriptionally activating BZW2 (basic leucine zipper and W2 domains 2) to induce the oncogenic AKT pathway. Moreover, the transcriptional activity of TEAD4 was independent of its canonical coactivators YAP/TAZ. Clinically, TEAD4 serves as an independent predictor of unfavorable prognosis and cisplatin response in NPC. Our data revealed the crucial role of TEAD4 in driving tumor malignancy, thus, may provide therapeutic vulnerability in NPC.

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Section: Methodsmentioning

confidence: 99%

TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma

Wang

Wei

et al. 2023

Sci. Adv.

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“… 684 , 685 Elevated palmitoylation of NOD2 mutants in autoinflammatory diseases leads to inflammation and inhibits autophagic degradation (Figure 11 ). 686 In autoimmune diseases, palmitoylation activates the STING signal associated with the type I IFN response and induces the expression of inflammatory genes through recruitment of TBK1 and IRF3. Treatment with the palmitoylation inhibitor 2‐bromopalmitate (2‐BP) can abolish the type I IFN response by inhibiting the palmitoylation of STING.…”

Section: Long‐chain Fatty Acid Modificationsmentioning

confidence: 99%

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

Zhong

Xiao

Xie

et al. 2023

MedComm

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Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well‐known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short‐chain and long‐chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.

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“…Mechanistically, the NOD2s‐R444C mutation possesses an enhanced ability to combine with ZDHHC5, making it more easily S‐palmitoylated. Increased S‐palmitoylation of NOD2s‐R444C inhibits the cargo receptor SQSTM1/p62‐NOD2s‐R444C association, leading to impaired SQSTM1/p62‐mediated autophagic degradation of NOD2 and excessive inflammation [139]. ZDHHC5 deficiency can significantly decrease the NOD2s‐R444C‐triggered inflammatory response, suggesting that ZDHHC5 might serve as a potential therapeutic target for these AID patients.…”

Section: S‐palmitoylation Of Proteins In Innate Immunitymentioning

confidence: 99%

S‐palmitoylation regulates innate immune signaling pathways: molecular mechanisms and targeted therapies

2023

Self Cite

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S‐palmitoylation is a reversible posttranslational lipid modification that targets cysteine residues of proteins and plays critical roles in regulating the biological processes of substrate proteins. The innate immune system serves as the first line of defense against pathogenic invaders and participates in the maintenance of tissue homeostasis. Emerging studies have uncovered the functions of S‐palmitoylation in modulating innate immune responses. In this review, we focus on the reversible palmitoylation of innate immune signaling proteins, with particular emphasis on its roles in the regulation of protein localization, protein stability, and protein–protein interactions. We also highlight the potential and challenge of developing therapies that target S‐palmitoylation or de‐palmitoylation for various diseases.

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Palmitoylation restricts SQSTM1/p62-mediated autophagic degradation of NOD2 to modulate inflammation

Cited by 28 publications

References 38 publications

TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma

TEAD4 is a master regulator of high-risk nasopharyngeal carcinoma

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

S‐palmitoylation regulates innate immune signaling pathways: molecular mechanisms and targeted therapies

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