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| 1 | S-palmitoylation regulates AMPA receptors trafficking and function: a novel insight into synaptic regulation and therapeutics显示文摘Glutamate acting on AMPA-type ionotropic glutamate receptor(AMPAR) mediates the majority of fast excitatory synaptic transmission in the mammalian central nervous system. Dynamic regulation of AMPAR by post-translational modifications is one of the key elements that allow the nervous system to adapt to environment stimulations. S-palmitoylation, an important lipid modification by post-translational addition of a long-chain fatty acid to a cysteine residue, regulates AMPA receptor trafficking, which dynamically affects multiple fundamental brain functions, such as learning and memory. In vivo, S-palmitoylation is controlled by palmitoyl acyl transferases and palmitoyl thioesterases.In this review, we highlight advances in the mechanisms for dynamic AMPA receptors palmitoylation,and discuss how palmitoylation affects AMPA receptors function at synapses in recent years.Pharmacological regulation of S-palmitoylation may serve as a novel therapeutic strategy for neurobiological diseases. | Jun Han Pengfei Wu Fang Wang Jianguo Chen | 2015 | Acta Pharmaceutica Sinica B2015，5，1： | 6 |
| 2 | Modulating effects of acyl-CoA synthetase 5-derived mitochondrial Wnt2B palmitoylation on intestinal Wnt activity显示文摘AIM:To investigate the role of acyl-CoA synthetase 5(ACSL5)activity in Wnt signaling in intestinal surface epithelia.METHODS:Several cell lines were used to investigate the ACSL5-dependent expression and synthesis of Wnt2B,a mitochondrially expressed protein of the Wnt signaling family.Wnt activity was functionally assessed with a luciferase reporter assay.ACSL5-related biochemical Wnt2B modifications were investigatedwith a modified acyl-exchange assay.The findings from the cell culture models were verified using an Apcmin/+mouse model as well as normal and neoplastic diseased human intestinal tissues.RESULTS:In the presence of ACSL5,Wnt2B was unable to translocate into the nucleus and was enriched in mitochondria,which was paralleled by a significant decrease in Wnt activity.ACSL5-dependent S-palmitoylation of Wnt2B was identified as a molecular reason for mitochondrial Wnt2B accumulation.In cell culture systems,a strong relation of ACSL5 expression,Wnt2B palmitoylation,and degree of malignancy were found.Using normal mucosa,the association of ACSL5 and Wnt2B was seen,but in intestinal neoplasias the mechanism was only rudimentarily observed.CONCLUSION:ACSL5 mediates antiproliferative activities via Wnt2B palmitoylation with diminished Wnt activity.The molecular pathway is probably relevant for intestinal homeostasis,overwhelmed by other pathways in carcinogenesis. | Christina Klaus Ursula Schneider Christian Hedberg Anke K Schütz Jürgen Bernhagen Herbert Waldmann Nikolaus Gassler Elke Kaemmerer | 2014 | World Journal of Gastroenterology2014，20，40： | 4 |
| 3 | A cell wall-localized NLR confers resistance to Soybean mosaic virus by recognizing viral-encoded cylindrical inclusion protein.显示文摘Soybean mosaic virus (SMV) causes severe yield losses and seed quality reduction in soybean (Glycine max) production worldwide. Rsc4 from cultivar Dabaima is a dominant genetic locus for SMV resistance, and its mapping interval contains three Nucleotide-binding domain Leucine-rich Repeat containing (NLR) candidates (Rsc4-1, Rsc4-2, and Rsc4-3). The NLR-type resistant proteins were considered as important intracellular pathogen sensors in the previous studies. In this research, based on transient expression assay in Nicotiana benthamiana leaves, we found that the longest transcript of Rsc4-3 is sufficient to induce resistance response to SMV;and CRISPR/Cas9-mediated Rsc4-3 knockout in resistant cultivar Dabaima compromised the resistance. These indicate that Rsc4-3 confers resistance to SMV. Interestingly, Rsc4-3 encodes a cell wall localized NLR-type resistant protein (Rsc4-3). The internal polypeptide region responsible for apoplastic targeting of Rsc4-3 and the putative palmitoylation sites on the N-terminus are essential for the resistance response. Furthermore, we showed that viral-encoded cylindrical inclusion (CI) protein partially localizes to the cell wall and can interact with Rsc4-3. Virus-driven or transient expression of CI protein of avirulent SMV strains is enough to induce resistance response in the presence of Rsc4-3, suggesting that CI is the avirulent gene for Rsc4-3 mediated resistance. Our work exhibited a case of NLR recognizing virus in the apoplast and provided a simple and effective method for identifying resistant genes against SMV infection. | Jinlong Yin Liqun Wang Tongtong Jin Yang Nie Hui Liu Yanglin Qiu Yunhua Yang Bowen Li Jiaojiao Zhang Dagang Wang Kai Li Kai Xu Haijian Zhi | 2021 | Molecular Plant2021，14，11： | 2 |
| 4 | STING palmitoylation as a therapeutic target显示文摘Gain-of-function mutations in the STING-encoding gene TMEM173 are central to the pathology of the autoinflammatory disorder STING-associated vasculopathy with onset in infancy(SAVI).Furthermore,excessive activity of the STING signaling pathway is associated with autoinflammatory diseases,including systemic lupus erythematosus and Aicardi–Goutières syndrome(AGS).Two independent studies recently identified pharmacological inhibitors of STING.Strikingly,both types of compounds are reactive nitrocontaining electrophiles that target STING palmitoylation,a posttranslational modification necessary for STING signaling.As a consequence,the activation of downstream signaling molecules and the induction of type I interferons were inhibited.The compounds were effective at ameliorating inflammation in a mouse model of AGS and in blocking the production of type I interferons in primary fibroblasts from SAVI patients.This mini-review focuses on the roles of palmitoylation in STING activation and signaling and as a pharmaceutical target for drug development. | Anne Louise Hansen Kojiro Mukai Francisco J.Schopfer Tomohiko Taguchi Christian K.Holm | 2019 | Cellular & Molecular Immunology2019，16，3： | 1 |
| 5 | IFNγsignaling integrity in colorectal cancer immunity and immunotherapy显示文摘The majority of colorectal cancer patients are not responsive to immune checkpoint blockade(ICB).The interferon gamma(IFNγ)signaling pathway drives spontaneous and ICB-induced antitumor immunity.In this review,we summarize recent advances in the epigenetic,genetic,and functional integrity of the IFNγsignaling pathway in the colorectal cancer microenvironment and its immunological relevance in the therapeutic efficacy of and resistance to ICB.Moreover,we discuss how to target IFNγsignaling to inform novel clinical trials to treat patients with colorectal cancer. | Wan Du Timothy L.Frankel Michael Green Weiping Zou | 2022 | Cellular & Molecular Immunology2022，19，1： | 1 |
| 6 | Mutational analysis of hepatitis E virus ORF1 'Y-domain' : Effects on RNA replication and virion infectivity显示文摘AIM To investigate the role of non-structural open reading frame 1 'Y-domain' sequences in the hepatitis E virus(HEV) life cycle.METHODS Sequences of human HEV Y-domain(amino acid sequences 216-442) and closely-related viruses were analyzed in silico. Site-directed mutagenesis of the Y-domain(HEV SAR55) was carried out and studied in the replicon-baculovirus-hepatoma cell model. In vitro transcribed m RNA(p SK-GFP) constructs were transfected into S10-3 cells and viral RNA replicating GFP-positive cells were scored by flow cytometry. Mutant virions' infectivity was assayed on na?ve Hep G2/C3 A cells.RESULTS In silico analysis identified a potential palmitoylation-site(C336C337) and an α-helix segment(L410Y411S412W413L414F415E416) in the HEV Y-domain. Molecular characterization of C336 A, C337 A and W413 A mutants of the three universally conserved residues showed non-viability. Further, of the 10 consecutive saturation mutants covering the entire Y-domain nucleotide sequences(nts 650-1339), three constructs(nts 788-994) severely affected virus replication. This revealed the indispensability of the internal sequences but not of the up- or downstream sequences at the transcriptional level. Interestingly, the three mutated residues corresponded to thedownstream codons that tolerated saturation mutation, indicating their post-translational functional/structural essentiality. In addition, RNA secondary structure prediction revealed formation of stable hairpins(nts 788-994) where saturation mutation drastically inhibited virion infectivity. CONCLUSION This is the first demonstration of the critical role of Y-domain sequences in HEV life cycle, which may involve gene regulation and/or membrane binding in intracellular replication complexes. | Mohammad Khalid Parvez | 2017 | World Journal of Gastroenterology2017，23，4： | 1 |
| 7 | In vitro palmitoylation of native bovine brain G_oα显示文摘The native Goα was purified from bovine brain cortex and palmitoylated in vitro. The in vitro palmitoylation site was the same as that in vivo. The internal palmitoylation of purified native Goα was found to be largely maintained. The apparent palmitoylation ratio was significantly increased after the Goα was treated with DTT. The GTPγS binding characteristic of Goα was not influenced by palmitoylation, however, the affinity for LUVs was increased dramatically. The in vitro palmitoylation model of Goα provides a better basis for studying the functional role of G protein palmitoylation in signal transduction. | 杨胜于 黄有国 | 2000 | Science China(Life Sciences)2000，43，5： | 1 |
| 8 | ACSL5,a prognostic factor in acute myeloid leukemia,modulates the activity of Wnt/β-catenin signaling by palmitoylation modification显示文摘Acyl-CoA synthetase long chain family member 5(ACSL5),is a member of the acyl-CoA synthetases(ACSs)family that activates long chain fatty acids by catalyzing the synthesis of fatty acyl-CoAs.The dysregulation of ACSL5 has been reported in some cancers,such as glioma and colon cancers.However,little is known about the role of ACSL5 in acute myeloid leukemia(AML).We found that the expression of ACSL5 was higher in bone marrow cells from AML patients compared with that from healthy donors.ACSL5 level could serve as an independent prognostic predictor of the overall survival of AML patients.In AML cells,the ACSL5 knockdown inhibited cell growth both in vitro and in vivo.Mechanistically,the knockdown of ACSL5 suppressed the activation of the Wnt/β-catenin pathway by suppressing the palmitoylation modification of Wnt3a.Additionally,triacsin c,a pan-ACS family inhibitor,inhibited cell growth and robustly induced cell apoptosis when combined with ABT-199,the FDA approved BCL-2 inhibitor for AML therapy.Our results indicate that ACSL5 is a potential prognosis marker for AML and a promising pharmacological target for the treatment of molecularly stratified AML. | Wenle Ye Jinghan Wang Jiansong Huang Xiao He Zhixin Ma Xia Li Xin Huang Fenglin Li Shujuan Huang Jiajia Pan Jingrui Jin Qing Ling Yungui Wang Yongping Yu Jie Sun Jie Jin | 2023 | Frontiers of Medicine2023，17，4： | 0 |
| 9 | CD82 palmitoylation site mutations at Cys5+Cys74 affect EGFR internalization and metabolism through recycling pathway显示文摘Tetraspanin CD82 often participates in regulating the function of epidermal growth factor receptor(EGFR)and hepatocyte growth factor receptor(c-Met).Palmitoylation is a post-translational modification that contributes to tetraspanin web formation and affects tetraspanin-dependent cell signaling.However,the molecular mechanisms by which CD82 palmitoylation affects the localization and stability of EGFR and c-Met have not yet been elucidated.This study focuses on the expression and distribution of EGFR and c-Met in breast cancer as well as the related metabolic pathways and molecular mechanisms associated with different CD82 palmitoylation site mutations.The results show that CD82 with a palmitoylation mutation at Cys5+Cys74 can promote the internalization of EGFR.EGFR is internalized and strengthened by direct binding to CD82 with the tubulin assistance and located at the recycling endosome.After studying the recycling pathway marker proteins Rab11a and FIP2,we found that formation of the EGFR/CD82/Rab11a/FlP2 complex promotes the internalization and metabolism of EGFR through the recycling pathway and results in the re-expression of EGFR and CD82 on the cell membrane. | Jingya Bu Weiliang Zhong Meixian Li Shuiqing He Mingzhe Zhang Yu Zhang Ying Li | 2022 | Acta Biochimica et Biophysica Sinica2022，54，3： | 0 |
| 10 | Palmitoylation of GNAQ/11 is critical for tumor cell proliferation and survival in GNAQ/11-mutant uveal melanoma显示文摘More than 85%of patients with uveal melanoma(UM)carry a GNAQ or GNA11 mutation at a hotspot codon(Q209)that encodes G proteinαsubunit q/11 polypeptides(Gα_(q/11)).GNAQ/11 relies on palmitoylation for membrane association and signal transduction.Despite the palmitoylation of GNAQ/11 was discovered long before,its implication in UM remains unclear.Here,results of palmitoylation-targeted mutagenesis and chemical interference approaches revealed that the loss of GNAQ/11 palmitoylation substantially affected tumor cell proliferation and survival in UM cells.Palmitoylation inhibition through the mutation of palmitoylation sites suppressed GNAQ/11^(Q209L)-induced malignant transformation in NIH3T3 cells.Importantly,the palmitoylation-deficient oncogenic GNAQ/11 failed to rescue the cell death initiated by the knock down of endogenous GNAQ/11 oncogenes in UM cells,which are much more dependent on Gα_(q/11) signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations.Furthermore,the palmitoylation inhibitor,2-bromopalmitate,also specifically disrupted Gα_(q/11) downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/11-mutant UM cells and showed a notable synergistic effect when applied in combination with the BCL2 inhibitor,ABT-199,in vitro.The findings validate that GNAQ/11 palmitoylation plays a critical role in UM and may serve as a promising therapeutic target for GNAQ/11-driven UM. | Yan Zhang Baoyuan Zhang Yongyun Li Yuting Dai Jiaoyang Li Donghe Li Zhizhou Xia Jianming Zhang Ping Liu Ming Chen Bo Jiao Ruibao Ren | 2022 | Frontiers of Medicine2022，16，5： | 0 |
| 11 | Post-translational modification of KRAS: potential targets for cancer therapy显示文摘Aberrant activation of the RAS superfamily is one of the critical factors in carcinogenesis.Among them,KRAS is the most frequently mutated one which has inspired extensive studies for developing approaches to intervention.Although the cognition toward KRAS remains far from complete,mounting evidence suggests that a variety of post-translational modifications regulate its activation and localization.In this review,we summarize the regulatory mode of post-translational modifications on KRAS including prenylation,post-prenylation,palmitoylation,ubiquitination,phosphorylation,SUMOylation,acetylation,nitrosylation,etc.We also highlight the recent studies targeting these modifications having exhibited potent anti-tumor activities. | Wei-hua Wang Tao Yuan Mei-jia Qian Fang-jie Yan Liu Yang Qiao-jun He Bo Yang Jin-jian Lu Hong Zhu | 2021 | Acta Pharmacologica Sinica2021，42，8： | 0 |
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