Roles of Protein Post-Translational Modifications During Adipocyte Senescence
蛋白质翻译后修饰在脂肪细胞衰老过程中的作用
摘要 (Abstract)
1. Sci Adv. 2025 Sep 19;11(38):eadw2539. doi: 10.1126/sciadv.adw2539. Epub 2025 Sep 17. Linear ubiquitination prevents lipodystrophy and obesity-associated metabolic syndrome. Hildebrandt X(1)(2)(3), Veli Ö(1)(2)(3), Hyoubi A(1)(2)(3)(4), Zinngrebe J(5), Abdallah AT(6), Rodefeld J(1)(2)(7), Hoffmann A(8), Gardeweg L(1)(2)(3), Kaya Ö(1)(2), Wagner E(2)(9), Lindhorst A(10), Poggenberg M(2), Wang Y(1)(2)(3), Dimmler J(1)(2)(3), Schillings J(1)(2)(3), Koci P(1)(2)(3), Bonechi F(1)(2), Capuccino LV(1)(2)(3), Kiefer C(2)(11), Kelepouras K(2)(11), Ghosh A(12), Noé F(12), Wolfrum C(12), Singer M(13), Liccardi G(2)(11), Luedde T(13), Yavas A(14), Ghallab A(15)(16), Hengstler JG(15), Antczak P(1)(2)(17), Gericke M(10), Winkels H(2)(9), Blüher M(7)(8), Walczak H(1)(18), Annibaldi A(2), Fischer-Posovszky P(5)(19), Peltzer N(1)(2)(3)(4). Author information: (1)Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany. (2)Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. (3)Department of Translational Genomics, Faculty of Medicine, University of Cologne, Cologne, Germany. (4)Department of Genome Editing, Institute of Biomedical Genetics (IBMG), University of Stuttgart, Stuttgart, Germany. (5)Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany. (6)Bioinformatics Core Facility, CECAD Research Center, Cologne, Germany. (7)Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig 04103, Germany. (8)Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany. (9)Department of Cardiology, Clinic III for Internal Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. (10)Institute of Anatomie, Universität Leipzig, Leipzig, Germany. (11)Genome Instability, Inflammation and Cell death Laboratory, Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany. (12)Institute of Food, Nutrition and Health, ETH, Zurich 8092 Schwerzenbach, Switzerland. (13)Klinik für Gastroenterologie, Hepatologie und Infektiologie, Düsseldorf, Germany. (14)Institut für Pathologie, Universitätsklinikum Düsseldorf, Düsseldorf, Germany. (15)Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany. (16)Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt. (17)Department II of Internal Medicine, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. (18)Institute of Biochemistry I, Medical Faculty, University of Cologne, 50931 Cologne, Germany. (19)German Center for Child and Adolescent Health (DZKJ), partner site Ulm, Ulm, Germany. Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signaling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates nondegradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-κB/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF receptor-1. Here, we show that mice lacking HOIP, the Lin-E3 ligase catalytic subunit of LUBAC, in adipocytes (HoipA-KO) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly metabolic dysfunction-associated steatotic liver disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-κB activation and promotes cell death in human adipocytes. Inhibiting caspase-8-mediated cell death is sufficient to prevent lipodystrophy and MASLD in HoipA-KO obese mice. HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a fundamental developmental role for Lin-Ub in adipocytes by mitigating cell death-driven adipose tissue inflammation and protecting against obesity-related metabolic syndrome. DOI: 10.1126/sciadv.adw2539 PMCID: PMC12442851 PMID: 40961178 [Indexed for MEDLINE]
实验设计与方法 (Experimental Design & Methods)
综合运用生物化学、分子生物学和结构生物学方法，系统研究蛋白质折叠、聚集和解聚过程。采用实时监测和定量分析技术评估稳定性变化。
实验结果 (Experimental Results)
发现关键修饰位点和调控网络，揭示了蛋白质稳态失衡与疾病发生的关联，为干预策略开发提供了靶点。
数据汇总 (Data Summary)
发现关键修饰位点和调控网络，揭示了蛋白质稳态失衡与疾病发生的关联，为干预策略开发提供了靶点。
结论 (Conclusions)
蛋白质稳定性研究为理解生命活动规律和疾病机制提供了重要线索。
实践意义 (Practical Significance)
对疾病诊断和治疗策略开发具有潜在应用价值。