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Deep learning identification of novel autophagic protein-protein interactions and experimental validation of Beclin 2-Ubiquilin 1 axis in triple-negative breast cancer

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Oncology research 2025年第1期33卷 67-81页

作者： Xiang Li Wenke Jin Lifeng Wu Huan Wang Xin Xie Wei Huang B O Liu State Key Laboratory of Southwestern Chinese Medicine Resources School of Pharmacy and College of Medical Technology Chengdu University of Traditional Chinese Medicine Chengdu 611137 China. department of biotherapy Cancer Center and State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 China.

Background:Triple-negative breast cancer (TNBC), characterized by its lack of traditional hormone receptors and HER2, presents a significant challenge in oncology due to its poor response to conventional therapies. Autophagy is an important process for maintaining cellular homeostasis, and there are currently autophagy biomarkers that play an effective role in the clinical treatment of tumors. In contrast to targeting protein activity, intervention with protein-protein interaction (PPI) can avoid unrelated crosstalk and regulate the autophagy process with minimal interference pathways.Methods:Here, we employed Naive Bayes, Decision Tree, and k-Nearest Neighbors to elucidate the complex PPI network associated with autophagy in TNBC, aiming to uncover novel therapeutic targets. Meanwhile, the candidate proteins interacting with Beclin 2 were initially screened in MDA-MB-231 cells using Beclin 2 as bait protein by immunoprecipitation-mass spectrometry assay, and the interaction relationship was verified by molecular docking and CO-IP experiments after intersection. Colony formation, cellular immunofluorescence, cell scratch and 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) tests were used to predict the clinical therapeutic effects of manipulating candidate PPI.Results:By developing three PPI classification models and analyzing over 13,000 datasets, we identified 3733 previously unknown autophagy-related PPIs. Our network analysis revealed the central role of Beclin 2 in autophagy regulation, uncovering its interactions with 39 newly identified proteins. Notably, the CO-IP studies identified the substantial interaction between Beclin 2 and Ubiquilin 1, which was anticipated by our model and discovered in immunoprecipitation-mass spectrometry assay results. Subsequently, investigations showed that overexpressing Beclin 2 increased Ubiquilin 1, promoted autophagy-dependent cell death, and inhibited proliferation and metastasis in MDA-MB-231 cells.

关键词： Artificial intelligence (AI) Autophagy Beclin 2 Protein-protein interactions (PPI) Triple-negative breast cancer (TNBC) Ubiquilin 1

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Understanding the link between type 2 diabetes mellitus and Parkinson's disease:role of brain insulin resistance

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Neural Regeneration Research 2025年第11期20卷 3113-3123页

作者： Theodora Ntetsika Sergiu-Bogdan Catrina Ioanna Markaki department of clinical Neuroscience Karolinska InstituteStockholmSweden department of Neurology Karolinska University HospitalStockholmSweden department of Molecular Medicine and Surgery Karolinska InstituteStockholmSweden center for Diabetes Academic Specialist CenterStockholmSweden center for Neurology Academic Specialist CenterStockholmSweden

Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic *** data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular *** insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological *** contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.

关键词： brain insulin resistance brain insulin signaling diabetes type 2 GLP-1 receptor agonists GLP-1 signaling insulin resistance insulin signaling neurodegeneration Parkinson's disease targeted therapy

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Immunosuppressive checkpoint Siglec-15:a vital new piece of the cancer immunotherapy jigsaw puzzle

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Cancer Biology & Medicine 2019年第2期16卷 205-210页

作者： Xiubao Ren department of biotherapy Tianjin Medical University Cancer Institute & Hospital National Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin Key Laboratory of Cancer Immunology and biotherapy Tianjin’s Clinical Research Center for Cancer

On March 5th, a novel immunosuppressive molecule,Siglec-15, was reported in Nature Medicine by Professor Lieping Chen1. Siglec-15 was reported in a wide variety of tumors. The molecule is not a simple replica of PD-1/***, the expressions of Siglec-15 and PD-L1 are mutually exclusive1, suggesting that Siglec-15 antibodies may be effective on tumors that are not responsive to anti-PD-1/PDL1 therapy. Siglec-15 potentially serves as a complementary therapeutic target and offers alternative treatments for many anti-PD-l/PD-Ll therapy unresponsive patients. This discovery generated a huge response.

关键词： cancer immunotherapy

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Spastin and alsin protein interactome analyses begin to reveal key canonical pathways and suggest novel druggable targets

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Neural Regeneration Research 2025年第3期20卷 725-739页

作者： Benjamin R.Helmold Angela Ahrens Zachary Fitzgerald P.Hande Ozdinler department of Neurology Feinberg School of MedicineNorthwestern UniversityChicagoILUSA center for Molecular Innovation and Drug Discovery Center for Developmental TherapeuticsChemistry of Life Processes InstituteNorthwestern UniversityEvanstonILUSA Mesulam center for Cognitive Neurology and Alzheimer’s Disease Feinberg School of MedicineNorthwestern UniversityChicagoILUSA Feinberg School of Medicine Les Turner ALS Center at Northwestern UniversityChicagoILUSA

Developing effective and long-term treatment strategies for rare and complex neurodegenerative diseases is challenging. One of the major roadblocks is the extensive heterogeneity among patients. This hinders understanding the underlying disease-causing mechanisms and building solutions that have implications for a broad spectrum of patients. One potential solution is to develop personalized medicine approaches based on strategies that target the most prevalent cellular events that are perturbed in patients. Especially in patients with a known genetic mutation, it may be possible to understand how these mutations contribute to problems that lead to neurodegeneration. Protein–protein interaction analyses offer great advantages for revealing how proteins interact, which cellular events are primarily involved in these interactions, and how they become affected when key genes are mutated in patients. This line of investigation also suggests novel druggable targets for patients with different mutations. Here, we focus on alsin and spastin, two proteins that are identified as “causative” for amyotrophic lateral sclerosis and hereditary spastic paraplegia, respectively, when mutated. Our review analyzes the protein interactome for alsin and spastin, the canonical pathways that are primarily important for each protein domain, as well as compounds that are either Food and Drug Administration–approved or are in active clinical trials concerning the affected cellular pathways. This line of research begins to pave the way for personalized medicine approaches that are desperately needed for rare neurodegenerative diseases that are complex and heterogeneous.

关键词： ALS2 alsin amyotrophic lateral sclerosis hereditary spastic paraplegia neurodegenerative diseases personalized medicine precision medicine protein interactome protein-protein interactions SPAST spastin

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Nanoparticle delivery for central nervous system diseases and its clinical application

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Nano Research 2024年第7期17卷 6305-6322页

作者： Lin Tang Rui Zhang Yusi Wang Mohan Liu Die Hu Yuanda Wang Li Yang department of biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

In the treatment of central nervous system(CNS)diseases such as glioma,Alzheimer's disease(AD)and Parkinson's disease(PD),drugs are expected to reach specific areas of the brain to achieve the desired *** a growing number of therapeutic targets have been identified in preclinical studies,the ones that can ultimately be used in the clinic are ***,the research process and clinical application of drugs for treating CNS diseases are still large *** barriers such as the blood‒brain barrier(BBB)act as selective permeable membranes,allowing only certain molecules to enter the brain;this barrier is the major obstacle restricting the arrival of most drugs to brain ***,nanoparticles,including lipid-based,cell-derived biomimetic,polymeric and inorganic nanoparticles,have gained increasing attention because of their ability to cross physiological barriers,and could play an important role as delivery carriers and ***,clinical applications of nanoparticles in CNS diseases are *** review focuses on the progress of current research on the use of nanoparticles for the treatment of CNS diseases to provide additional insight into the treatment of CNS diseases.

关键词： nanoparticles central nervous system(CNS)diseases clinical applications delivery carriers immunomodulators

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Exhausted T cells and epigenetic status

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Cancer Biology & Medicine 2020年第4期17卷 923-936页

作者： Ziqing Zeng Feng Wei Xiubao Ren department of Immunology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of biotherapy Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjin's Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China

Exhausted T cells are a group of dysfunctional T cells,which are present in chronic infections or *** most significant characteristics of exhausted T cells are attenuated effector cytotoxicity,reduced cytokine production,and upregulation of multiple inhibitory molecular receptors(e.g.,PD-1,TIM-3,and LAG-3).The intracellular metabolic changes,altered expression of transcription factors,and a unique epigenetic landscape constitute the exhaustion ***,researchers have made progress in understanding exhausted T cells,with the definition and identification of exhausted T cells changing from phenotypebased to being classified at the transcriptional and epigenetic *** studies have revealed that exhausted T cells can be separated into two subgroups,namely TCF1^(+)PD-1^(+)progenitor-like precursor exhausted cells and TCF1-PD-1^(+)terminally differentiated exhausted T ***,the progenitor-like precursor cell population may be a subset of T cells that can respond to *** have also found that TOX initiates and dominates the development of exhausted T cells at the transcriptional and epigenetic *** also maintains T cell survival and may affect decisions regarding treatment *** this review,we discuss the latest developments in T cell exhaustion in regards to definitions,subpopulations,development mechanisms,differences in diverse diseases,and treatment prospects for exhausted T ***,we hypothesize that the epigenetic state regulated by TOX might be the key point,which can determine the reversibility of exhaustion and the efficacy of immunotherapy.

关键词： T cell exhaustion TOX tumor immunity epigenetic landscape immunotherapy

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Insights into tertiary lymphoid structures in the solid tumor microenvironment: anti-tumor mechanism, functional regulation, and immunotherapeutic strategies

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Cancer Biology & Medicine 2021年第4期18卷 981-991页

作者： Hua Zhao Hao Wang Qiuru Zhou Xiubao Ren department of Immunology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of biotherapy Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China

Tertiary lymphoid structures(TLSs)are ectopic immune cell aggregations that develop in peripheral tissues in response to a wide range of chronic inflammatory conditions,including infection,autoimmune disease,and *** the tumor microenvironment(TME),the structures of TLSs,including B-cell-and T-cell-enriched areas indicate that the TLSs might be the local site during the initiation and maintenance of humoral and cellular immune responses against *** studies have evaluated the expression of TLSs in different cancer patients and their association with prognoses of cancer *** was shown that welldeveloped TLSs characterized by mature B cells synthesized tumor specific antibodies,which were considered as specific markers for a good ***,there are still some immunosuppressive factors existing in the TLSs that may affect anti-tumor *** factors include dysfunctional B cells,regulatory T cells,and T follicular regulatory *** complexity and heterogeneity of the TLS composition may affect the function and activity of TLSs;it is therefore essential to fully understand the function and influencing factors in *** has been reported that checkpoint inhibitors and vaccines are currently being developed to reprogram the TME by establishing mature TLSs to improve cancer *** this review,we focused on recent advances in TLSs in human solid tumors,including structural characteristics and classes,antitumor mechanisms,immunosuppressive factors,and TLSbased therapeutic approaches.

关键词： Tertiary lymphoid structure tumor microenvironment immunotherapy B cells T cells

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The SUMOylation of TAB2 mediated by TRIM60 inhibits MAPK/NF-κB activation and the innate immune response

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Cellular & Molecular Immunology 2021年第8期18卷 1981-1994页

作者： Zhiwen Gu Xueying Chen Wenyong Yang Yu Qi Hui Yu Xiaomeng Wang Yanqiu Gong Qianqian Chen Bo Zhong Lunzhi Dai Shiqian Qi Zhiqiang Zhang Huiyuan Zhang Hongbo Hu department of Rheumatology and Immunology National Clinical Research Center for GeriatricsState Key Laboratory of BiotherapyWest China HospitalSichuan Universityand Collaborative Innovation Center of BiotherapyChengdu610041China department of Virology College of Life SciencesDepartment of ImmunologyMedical Research InstituteWuhan UniversityWuhan430072China department of General Practice and Lab of PTM State Key Laboratory of BiotherapyWest China HospitalSichuan Universityand Collaborative Innovation Center of BiotherapyChengdu610041China department of Urology State Key Laboratory of BiotherapyWest China HospitalSichuan Universityand Collaborative Innovation Center of BiotherapyChengdu610041China Immunobiology and Transplant Science center Houston Methodist HospitalHoustonTXUSA77030

Activation of the TAK1 signalosome is crucial for mediating the innate immune response to pathogen invasion and is regulated by multiple layers of posttranslational modifications,including ubiquitination,SUMOylation,and phosphorylation;however,the underlying molecular mechanism is not fully *** this study,TRIM60 negatively regulated the formation and activation of the TAK1 *** of TRIM60 in macrophages led to enhanced MAPK and NF-κB activation,accompanied by elevated levels of proinflammatory cytokines but not ***-mass spectrometry assays identified TAB2 as the target of TRIM60 for SUMOylation rather than ubiquitination,resulting in impaired formation of the TRAF6/TAB2/TAK1 complex and downstream MAPK and NF-κB *** SUMOylation sites of TAB2 mediated by TRIM60 were identified as K329 and K562;substitution of these lysines with arginines abolished the SUMOylation of *** vivo experiments showed that TRIM60-deficient mice showed an elevated immune response to LPS-induced septic shock and *** *** data reveal that SUMOylation of TAB2 mediated by TRIM60 is a novel mechanism for regulating the innate immune response,potentially paving the way for a new strategy to control antibacterial immune responses.

关键词： SUMOylation innate immune response TRAM60 TAB2

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Morphine-3-glucuronide upregulates PD-L1 expression via TLR4 and promotes the immune escape of non-small cell lung cancer

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Cancer Biology & Medicine 2021年第1期18卷 155-171页

作者： Kaiyuan Wang Jian Wang Ting Liu Wenwen Yu Nan Dong Chen Zhang Wenbin Xia Feng Wei Lili Yang Xiubao Ren department of Anesthesiology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of Immunology Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of Cancer Biobank Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China department of biotherapy Tianjin Medical University Cancer Institute and HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin’s Clinical Research Center for CancerKey Laboratory of Cancer Immunology and BiotherapyTianjin 300060China

Objective:Patients with cancer pain are highly dependent on morphine analgesia,but studies have shown a negative correlation between morphine demand and patient *** long-term use of morphine may result in abnormally elevated serum morphine-3-glucuronide(M3G)***,the effects of M3G on tumor progression are worth ***:The effects of M3G on PD-L1 expressions in human non-small cell lung cancer(NSCLC)cell lines were first *** of TLR4 downstream pathways after M3G treatment was then determined by Western *** effects of M3G on human cytotoxic T lymphocytes(CTL)cytotoxicity and INF-γrelease was also ***,the LLC murine lung adenocarcinoma cell line were used to establish a murine lung cancer model,and the effects of M3G on tumor growth and metastasis were ***:M3G promoted the expressions of PD-L1 in the A549 and H1299 cell lines in a TLR4-dependent manner(P<0.05).M3G activated the PI3 K and the NFκB signaling pathways,and this effect was antagonized by a TLR4 pathway inhibitor.A PI3 K pathway inhibitor reversed the M3G-mediated PD-L1 upregulation.M3G inhibited the cytotoxicity of CTL on A549 cells and decreased the level of INF-γ.Repeated M3G intraperitoneal injections promoted LLC tumor growth and lung metastasis through the upregulation of tumor expressed PD-L1 and the reduction of CTL in the tumor ***:M3G specifically activated TLR4 in NSCLC cells and upregulated PD-L1 expression through the PI3 K signaling pathway,thereby inhibiting CTL cytotoxicity and finally promoting tumor immune escape.

关键词： Non-small cell lung cancer TLR4 PD-L1 morphine-3-glucuronide immune escape

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Mid1ip1b modulates apical reorientation of non-centrosomal microtubule organizing center in epithelial cells

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Journal of Genetics and Genomics 2018年第8期45卷 433-442页

作者： Xin Zhou Chun Xiao Yu Li Yanna Shang Dongqin Yin Siying Li Bo Xiang Ran Lu Yi Ji Yang Wu Wentong Meng Hongyan Zhu Jin Liu Huozhen Hu Xianming Mo Hong Xu department of Pediatric Surgery and Laboratory of Stem Cell Biology State Key Laboratory of Biotherapy West China Hospital Sichuan University and Collaborative Innovation Center for Biotherapy National clinical Research center of Geriatrics West China Hospital Sichuan University

In most kinds of animal cells, the centrosome serves as the main microtubule organizing center （MTOC） that nucleates microtubule arrays throughout the cytoplasm to maintain cell structure, cell division and intracellular transport. Whereas in epithelial cells, non-centrosomal MTOCs are established in the apical domain for generating asymmetric microtubule fibers and cilia in epithelial cells for the organ morphogenesis during embryonic development. However, the mechanism by which MTOCs localize to the apical domain in epithelial cells remains largely unknown. Here, we show that Mid liplb has a close interaction with γ-tubulin protein, the central component of MTOC, and modulates lumen opening of the neural tube, gut, intestine, and kidney of zebrafish. Knockdown or dominant negative effect of Mid 1ip 1 b resulted in failure of lumen formation of the organs as aforementioned. Moreover, the non-centrosomal MTOCs were unable to orientate to the apical domain in Midliplb knockdown epithelial cells, and the centrosomal MTOCs were inaccurately placed in the apical domain, resulting in defective formation of asymmetric microtubules and misplacement of cilia in the apical domain. These data uncover a molecule that controls the proper localization of MTOCs in the apical domain in epithelial cells for organ morphogenesis during embryonic development.

关键词： Mid1ip1b Microtubule organizing center Non-centrosomal MTOC Microtubule Epithelial cell

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