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Tissue-resident macrophages exacerbate lung injury after remote sterile damage

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Cellular & Molecular Immunology 2024年第4期21卷 332-348页

作者： Hanhui Zhong Jingjing Ji Jinling Zhuang Ziying Xiong Pengyun Xie Xiaolei Liu Jundi Zheng Wangli Tian Xiaoyang Hong Jing Tang The Department of Anesthesiology Affiliated Hospital of Guangdong Medical UniversityZhanjiangGuangdongChina The Department of Critical Care Medicine General Hospital of Southern Theater Command of PLAGuangzhouChina The Department of Respiratory Medicine Guangdong Provincial Hospital of Integrated Chinese and Western MedicineFoshanChina Pediatric Intensive Care unit Senior Department of Pediatricsthe Seventh Medical Center of PLA General HospitalBeijingChina

Remote organ injury,which is a common secondary complication of sterile tissue damage,is a major cause of poor prognosis and is difficult to ***,we report the critical role of tissue-resident macrophages in lung injury after trauma or stroke through the inflammatory *** found that depleting tissue-resident macrophages rather than disrupting the recruitment of monocyte-derived macrophages attenuated lung injury after trauma or *** findings revealed that the release of circulating alarmins from sites of distant sterile tissue damage triggered an inflammatory response in lung-resident macrophages by binding to receptor for advanced glycation end products(RAGE)on the membrane,which activated epidermal growth factor receptor(EGFR).Mechanistically,ligand-activated RAGE triggered EGFR activation through an interaction,leading to Rab5-mediated RAGE internalization and EGFR phosphorylation,which subsequently recruited and activated P38;this,in turn,promoted RAGE translation and trafficking to the plasma membrane to increase the cellular response to RAGE ligands,consequently exacerbating *** study also showed that the loss of RAGE or EGFR expression by adoptive transfer of macrophages,blocking the function of RAGE with a neutralizing antibody,or pharmacological inhibition of EGFR activation in macrophages could protect against trauma-or stroke-induced remote lung ***,our study revealed that targeting the RAGE-EGFR signaling pathway in tissue-resident macrophages is a potential therapeutic approach for treating secondary complications of sterile damage.

关键词： tissue-resident macrophage RAGE remote sterile damage

AKT2^(S128)/CCTα^(S315/319/323)-positive cancer-associated fibroblasts (CAFs) mediate focal adhesion kinase (FAK) inhibitors resistance via secreting phosphatidylcholines (PCs)

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Signal Transduction and Targeted Therapy 2024年第2期9卷 782-796页

作者： Jie Chen Lingyuan Zhang Yuheng Zhu Di Zhao Jing Zhang Yanmeng Zhu Jingyuan Pang Yuanfan Xiao Qingnan Wu Yan Wang Qimin Zhan Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing) Laboratory of Molecular OncologyPeking University Cancer Hospital&Institute100142 BeijingChina Peking University International Cancer Institute Peking University100191 BeijingChina Research unit of Molecular Cancer Research Chinese Academy of Medical SciencesBeijingChina Soochow University Cancer Institute Suzhou 215000China Institute of Cancer Research Shenzhen Bay LaboratoryShenzhen 518107China

Abnormal metabolism is regarded as an oncogenic hallmark related to tumor progression and therapeutic *** study employed multi-omics,including phosphoproteomics,untargeted metabolomics and lipidomics,to demonstrate that the pAKT2 Ser128 and pCCTαSer315/319/323-positive cancer-associated fibroblasts(CAFs)substantially release phosphatidylcholines(PCs),contributing to the resistance of focal adhesion kinase(FAK)inhibitors in esophageal squamous cell carcinoma(ESCC)***,we observed extremely low levels of FAK Tyr397 expression in CAFs,potentially offering no available target for FAK inhibitors playing their anti-growth role in ***,FAK inhibitor increased the intracellular concentration of Ca2+in CAFs,promoting the formation of AKT2/CCTαcomplex,leading to phosphorylation of CCTαSer315/319/323 sites and eventually enhancing stromal PC *** activation could stimulate the intratumoral Janus kinase 2(JAK2)/Signal transducer and activator of transcription 3(STAT3)pathway,triggering resistance to FAK *** of clinical samples demonstrated that stromal pAKT2 Ser128 and pCCTαSer315/319/323 are related to the tumor malignancy and reduced patient ***-targeted lipidomics and further validation cohort quantitatively showed that plasma PCs enable to distinguish the malignant extent of ESCC *** conclusion,inhibition of stroma-derived PCs and related pathway could be possible therapeutic strategies for tumor therapy.

关键词： CAFs metabolism resistance

PROTAC mediated FKBP12 degradation enhances Hepcidin expression via BMP signaling without immunosuppression activity

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Signal Transduction and Targeted Therapy 2022年第6期7卷 1891-1894页

作者： Tianbai Zhong Xiuyun Sun Li Yu Yongbo Liu Xin Lin Yu Rao Wei Wu MOE Key Laboratory of protein Sciences Beijing Advanced Innovation Center for Structural BiologySchool of Life SciencesTsinghua UniversityBeijing 100084P.R.China MOE Key Laboratory of protein Sciences School of Pharmaceutical SciencesMOE Key Laboratory of Bioorganic Phosphorus Chemistry&Chemical BiologyTsinghua UniversityBeijing 100084China Institute for Immunology and School of Medicine Tsinghua UniversityBeijing 100084China

Dear Editor,Hepcidin is a 25-amino acid peptide acting as a pivotal negative regulator in iron homeostasis,which can bind to an iron exporter,ferroportin 1,and induce its internalization and degradation.1 Hepcidin is produced in hepatocytes mainly under the control of BMP ***2/6,secreted by liver endothelial cells in response to iron level,binds to BMP type I and type II receptors and triggers the phosphorylation of Smad1/5/8 which directly promotes hepcidin expression.1 The immunophilin family protein FKBP12 is associated with BMP type I receptors to prevent uncontrolled receptor activation.

关键词： Hepcidin FKBP12 BMP

Identifi cation and functional analysis of phosphorylation residues of the Arabidopsis BOTRYTIS-INDUCED KINASE1

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protein & Cell 2013年第10期4卷 771-781页

作者： Jinhua Xu Xiaochao Wei Limin Yan Dan Liu Yuanyuan Ma Yu Guo Chune Peng Honggang Zhou Cheng Yang Zhiyong Lou Wenqing Shui College of Life Sciences and Tianjin State Laboratory of protein Science Nankai UniversityTianjin 300071China High-throughput Molecular Drug Discovery Center Tianjin Joint Academy of Biotechnology and MedicineTianjin 300457China Laboratory of Structural Biology and MOE Laboratory of protein Science School of Medicine and Life SciencesTsinghua UniversityBeijing 100084China College of Pharmacy and State Key Laboratory of Medicinal Chemical Biology Nankai UniversityTianjin 300071China

Arabidopsis BOTRYTIS-INDUCED KINASE1(BIK1)is a receptor-like cytoplasmic kinase acting early in multiple signaling pathways important for plant growth and innate *** is known to form a signaling complex with a cell-surface receptor FLS2 and a co-receptor kinase BAK1 to transduce signals upon perception of pathogen-asso-ciated molecular patterns(PAMPs).Although site-specifi c phosphorylation is speculated to mediate the activation and function of BIK1,few studies have been devoted to complete profiling of BIK1 phosphorylation ***,we identified nineteen in vitro autophosphoryla-tion sites of BIK1 including three phosphotyrosine sites,thereby proving BIK1 is a dual-specifi city kinase for the fi rst *** kinase activity of BIK1 substitution mutants were explicitly assessed using quantitative mass spec-trometry(MS).Thr-237,Thr-242 and Tyr-250 were found to most signifi cantly affect BIK1 activity in autophosphoryla-tion and phosphorylation of BAK1 in vitro.A structural model of BIK1 was built to further illustrate the molecular functions of specifi c phosphorylation *** also mapped new sites of FLS2 phosphorylation by BIK1,which are different from those by *** in vitro results could provide new hypotheses for more in-depth in vivo studies leading to deeper understanding of how phosphorylation contributes to BIK1 activation and medi-ates downstream signaling specifi city.

关键词： phosphorylation BIK1 receptor-like cytop-lasmic kinase quantitative mass spectrometry

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Sleep as a window to understand and regulate Alzheimer's disease:emerging roles of thalamic reticular nucleus

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Neural Regeneration Research 2025年第6期20卷 1711-1712页

作者： Haoqi Sun Shiqian Shen Robert J.Thomas M.Brandon Westover Can Zhang Department of Neurology Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Center for Translational Pain Research Department of AnesthesiaCritical Care and Pain MedicineMassachusetis General HospitalHarvard Medical SchoolBostonMAUSA Division of Pulmonary Critical Care and Sleep MedicineDepartment of MedicineBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Genetics and Aging Research unit McCance Center for Brain HealthMass General Institute for Neurodegenerative DiseaseDepartment of NeurologyMassachusetts General HospitalHarvard Medical SchoolBostonMAUSA

Introduction:Alzheimer 's disease(AD) is a common neurodegenerative disorder and the primary cause of dementia. Considerable evidence supports the “amyloid hypothesis,” stating that the pathogenesis of AD is primarily caused by the deposition of amyloid-β(Aβ), which drives tau phosphorylation, neuroinflammation, and neurodegeneration in the brain. The amyloid hypothesis is strengthened by the significant and moderate benefit of lecanemab, a humanized antibody through an anti-amyloid mechanism,showing slowed clinical decline(van Dyck et al.,2023). The recent positive results of anti-amyloid trials have brought back focus on the amyloid hypothesis through biochemical, genetic, and pharmacological approaches(Zhang, 2023).

关键词： Alzheimer inflammation hypothesis

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Reversible phosphorylation of the 26S proteasome

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protein & Cell 2017年第4期8卷 255-272页

作者： Xing Guo Xiuliang Huang Mark J. Chen The Life Sciences Institute of Zhejiang University Hangzhou 310058 China Ministry of Education Key Laboratory of protein Science School of Life Sciences Tsinghua University Beijinq 100084 China Department of Bioinformatics and Computational Biology Genentech Inc. South San Francisco CA 94080 USA

The 26S proteasome at the center of the ubiquitin- proteasome system （UPS） is essential for virtually all cellular processes of eukaryotes. A common miscon- ception about the proteasome is that, once made, it remains as a static and uniform complex with sponta- neous and constitutive activity for protein degradation. Recent discoveries have provided compelling evidence to support the exact opposite insomuch as the 26S proteasome undergoes dynamic and reversible phos- phorylation under a variety of physiopathological con- ditions. In this review, we summarize the history and current understanding of proteasome phosphorylation, and advocate the idea of targeting proteasome kinases/ phosphatases as a new strategy for clinical interven- tions of several human diseases.

关键词： proteasome phosphorylation kinase,phosphatase protein degradation

Identification and the molecular mechanism of novel duck liver-derived anti-inflammatory peptides in LPS-induced RAW 264.7 cell model

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Food Science and Human Wellness 2023年

作者： Xiankang Fan Laidi Zhang Yangying Sun Changyu Zhou Qiang Xia Lihui Du Zhen Wu Daodong Pan Key Laboratory of Animal protein Food Processing Technology of Zhejiang Province College of Food and Pharmaceutical Sciences Ningbo University State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products Ningbo University

In this study， 10 novel anti-inflammatory peptides were identified from duck liver， and their molecular mechanism was demonstrated based on machine learning and molecular docking. Using Sephadex G-15 gel chromatography separation， reversed-phase high-performance liquid chromatography purification， liquid chromatography-tandem mass spectrometry identification， and Biopep database comparison， 10 novel anti-inflammatory peptides were initially found. Their splendid ACE inhibition and anti-inflammatory properties were confirmed by machine learning. With binding energies less than -5.0 kcal/mol， molecular docking revealed that they could efficiently bind to the active pockets of TNF-， IL-6， COX-2， and NF-B proteins with efficiency， indicating that the compounds can spontaneously form complexes through hydrogen bonding and hydrophobic interactions with the protein binding pockets. In the LPS-induced RAW 264.7 cell model， the release of NO， TNF-α， and IL-6 and the mRNA expression of inflammatory factors (TNF-α， IL-6， COX-2， and NF-κB) were significantly inhibited by these peptides. We concluded it might be due to their anti-inflammatory effects by inhibiting the protein phosphorylation of IκBα in the cytoplasm and preventing the translocation of NF-κB p65 in the cytoplasm to the nucleus， thereby regulating the NF-κB signaling pathway. This study is essential for the screening of anti-inflammatory peptides and the investigation of the mechanism of action.

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Detection of cardiac myosin binding protein-C (cMyBP-C) by a phospho-specific PKD antibody in contracting rat cardiomyocytes

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Advances in Bioscience and Biotechnology 2013年第4期4卷 1-6页

作者： Ellen Dirkx Freek G. Bouwman Didier Vertommen Edwin C. Mariman Sakthivel Sadayappan Jan F. C. Glatz Joost J. F. P. Luiken Guillaume J. van Eys Department of Cell and Molecular Physiology Stritch School of Medicine Loyola University Chicago USA Department of Human Biology Nutrition and Toxicology Research Institute Maastricht (NUTRIM) Maastricht University Maastricht The Netherlands Department of Molecular Genetics Cardiovascular Research Institute Maastricht (CARIM) Maastricht University Maastricht The Netherlands protein phosphorylation unit Université Catholique de Louvain Brussels Belgium

protein phosphorylation plays an important role in physiological processes, such as muscle contraction. Phospho-specific antibodies have become powerful tools to study these processes. Cardiac myosin binding protein-C (cMyBP-C) is one of the proteins that make up the contractile apparatus of cardiomyocytes. phosphorylation of cMyBP-C is essential for normal cardiac function, since dephosphorylation of this protein leads to its degradation and has been associated with cardiomyopathy. One of the upstream kinases, which phosphorylate cMyBP-C, is protein kinase D (PKD). While studying the role of PKD in cMyBP-C phosphorylation, we tried to analyze phosphorylation of PKD with a phospho-specific PKD-Ser744/748 antibody. Contrary to the expected 115 kDa, a signal was found for a 150-kDa protein. By MALDI-TOF mass spectrometry, we identified this protein to be cMyBP-C. These data were confirmed by immunostaining using the p-PKD-Ser744/748 antibody, which displayed a striated pattern similar to the one observed for a regular cMyBP-C antibody. To our knowledge there are no antibodies commercially available for phosphorylated cMyBP-C. Thus, the p-PKD-Ser744/748 antibody can accelerate research into the role of cMyBP-C phosphorylation in cardiomyocytes.

关键词： protein Kinase D Cardiac Myosin Binding protein-C Phospho-Specific Antibody protein phosphorylation

Reciprocal phosphorylation within receptor-like kinase complexes involved in plant growth and immune responses

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Reciprocal phosphorylation within receptor-like kinase compl...