Article
Biochemistry & Molecular Biology
Amalia Ruiz-Serrano, Christina N. Boyle, Josep M. Monne Rodriguez, Julia Guenter, Agnieszka E. Jucht, Svende Pfundstein, Andreas M. Bapst, Thomas A. Lutz, Roland H. Wenger, Carsten C. Scholz
Summary: Dysregulated energy metabolism is a major cause of various diseases. OTUB1 plays an important regulatory role in energy metabolism. Deletion of OTUB1 in mice leads to increased energy expenditure and improved glucose metabolism.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell Biology
Peiyi Xie, Qing Chao, Jiuang Mao, Yue Liu, Jiayu Fang, Jing Xie, Jing Zhen, Yongqi Ding, Bidong Fu, Yun Ke, Da Huang
Summary: The deubiquitinating enzyme OTUB1 plays a significant role in papillary thyroid carcinoma (PTC) by upregulating in PTC tissues and cells, and enhancing the proliferation ability of PTC cells through stabilizing EYA1 protein. This suggests that OTUB1 may be a novel therapeutic target for PTC.
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
(2021)
Article
Biochemistry & Molecular Biology
Ming Gao, Zijuan Qi, Min Deng, Hongyang Huang, Zhijie Xu, Guijie Guo, Jiajun Jing, Xiaofeng Huang, Ming Xu, Jake A. Kloeber, Sijin Liu, Jinzhou Huang, Zhenkun Lou, Jinxiang Han
Summary: The deubiquitinase USP7 plays a key role in controlling redox homeostasis by promoting HO-1 deubiquitination and stabilization in hepatocytes. USP7 inhibitor might be a potential therapeutic agent for treating HO-1 overexpressed liver cancers.
Article
Biochemistry & Molecular Biology
Aidana Sheryazdanova, Nivea Dias Amoedo, Sara Dufour, Francis Impens, Rodrigue Rossignol, Anna Sablina
Summary: The traditional understanding of aerobic glycolysis in cancer development has been challenged by the discovery of the important role of oxidative phosphorylation (OXPHOS). The study found that the increased expression of OXPHOS proteins in cancer cells is associated with high OXPHOS activity and sensitivity to OXPHOS inhibitors. The ubiquitin hydrolase OTUB1 was identified as a regulator of mitochondrial metabolism essential for lung cancer cell survival.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Article
Biochemistry & Molecular Biology
Jaemin Shin, Young Hun Kim, Bin Lee, Jae Ho Chang, Hee Youn Choi, Hoojung Lee, Ki Chan Song, Man Sup Kwak, Ji Eun Choi, Jeon-Soo Shin
Summary: Through various experiments, we found ubiquitin-specific protease 13 (USP13) as a novel binding partner of HMGB1 and demonstrated that USP13 plays a role in stabilizing HMGB1 from ubiquitin-mediated degradation. Further investigation showed that USP13 overexpression increased nucleocytoplasmic translocation of HMGB1 and promoted its secretion, which was inhibited by treatment with Spautin-1.
MOLECULAR MEDICINE
(2022)
Article
Oncology
Weifan Zhang, Weikun Qian, Jingtao Gu, Mengyuan Gong, Wunai Zhang, Simei Zhang, Cancan Zhou, Zhengdong Jiang, Jie Jiang, Liang Han, Xiaoqin Wang, Zheng Wu, Qingyong Ma, Zheng Wang
Summary: In this study, it was found that the lncRNA LINC00857 is significantly upregulated in pancreatic cancer (PC) and is associated with poor prognosis. Mutant p53 promotes the transcription of LINC00857, thereby promoting the metastasis of PC cells. LINC00857 binds to FOXM1 and OTUB1, inhibiting the degradation of FOXM1 and accelerating metastasis.
Article
Pharmacology & Pharmacy
Ruohan Zhang, Serra Ozgen, Hongke Luo, Judith Krigman, Yutong Zhao, Gang Xin, Nuo Sun
Summary: In this study, the researchers investigate the role of Parkin and USP30 in regulating the AKT/mTOR signaling during mitophagy. They found that Parkin inhibits AKT/mTOR signaling, while USP30 antagonizes the activity of Parkin to sustain AKT/mTOR activity.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Cell Biology
Diana Campos-Iglesias, Julia M. Fraile, Gabriel Bretones, Alejandro A. Montero, Elena Bonzon-Kulichenko, Jesus Vazquez, Carlos Lopez-Otin, Jose M. P. Freije
Summary: USP49 deubiquitinase is identified as a novel regulator of the spindle checkpoint. Loss of USP49 impairs proliferation and increases aneuploidy in cancer cell lines. USP49-depleted cells can overcome SAC-induced arrest in presence of nocodazole.
CELL DEATH & DISEASE
(2023)
Article
Gastroenterology & Hepatology
Jie-Lei Zhang, Bin-Bin Du, Dian-Hong Zhang, Huan Li, Ling-Yao Kong, Guang-Jian Fan, Ya-Peng Li, Peng-Cheng Li, Cui Liang, Zheng Wang, Lu-Lu Yang, Zheng-Yang Hao, Lei-Ming Wu, Zhen Huang, Jian-Zeng Dong, Jin-Ying Zhang, Rui Yao, Shou-Jun Wang, Yan-Zhou Zhang
Summary: OTUB1 plays a key role in NASH by inhibiting the polyubiquitination of TRAF6, thus reducing hepatic steatosis and inflammatory responses. Targeting the OTUB1-TRAF6-ASK1 axis could be a promising therapeutic strategy for NASH.
Article
Immunology
Floriana Mulas, Xu Wang, Shanshan Song, Gopala Nishanth, Wenjing Yi, Anna Brunn, Pia-Katharina Larsen, Berend Isermann, Ulrich Kalinke, Antonio Barragan, Michael Naumann, Martina Deckert, Dirk Schlueter
Summary: OTUB1 is identified as a potent novel regulator of DCs during infectious and inflammatory diseases. It promotes NF-kappa B activity, regulates cytokine production, and impacts the response to pathogens.
CELLULAR & MOLECULAR IMMUNOLOGY
(2021)
Article
Plant Sciences
Jing Sun, Wenzhong Song, Yuan Chang, Yanwei Wang, Tiegang Lu, Zhiguo Zhang
Summary: This study identified a rice lesion mimic mutant and investigated the regulatory mechanism of the lesion mimic phenotype. The results show that OsLMP1 modifies SA synthetic pathway genes by deubiquitination, thereby regulating the immune response in rice.
FRONTIERS IN PLANT SCIENCE
(2022)
Article
Multidisciplinary Sciences
Trisha A. Macrae, Miguel Ramalho-Santos
Summary: The study reveals a regulatory axis between the deubiquitinase Usp9x and PRC2 that is critical for self-renewal of mouse embryonic stem cells. Different levels of Usp9x lead to distinct chromatin and transcriptional patterns in ES cells, reminiscent of different developmental stages. Deletion of Usp9x in post-implantation embryos results in derepression of genes and morphological abnormalities, suggesting a crucial role of Usp9x-PRC2 axis in development.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Carla E. Cadena del Castillo, J. Thomas Hannich, Andres Kaech, Hirohisa Chiyoda, Jonathan Brewer, Masamitsu Fukuyama, Nils J. Faergeman, Howard Riezman, Anne Spang
Summary: The study reveals that the hedgehog signaling receptor PTCH functions as a cholesterol transporter. Reduction in PTCH activity leads to cellular cholesterol accumulation, resulting in changes in nuclear hormone receptor activity and fatty acid metabolism. This sheds light on the role of PTCH in maintaining organelle structure and fat metabolism.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Xue Han, Chune Ren, Chao Lu, Pengyun Qiao, Tingting Yang, Zhenhai Yu
Summary: OTUB1 is identified as a new deubiquitination enzyme for MYC protein degradation, promoting breast tumorigenesis by stabilizing MYC and enhancing its transcriptional activity and aerobic glycolysis.
CELL DEATH AND DIFFERENTIATION
(2022)
Article
Cell Biology
Yan Yan, Karl N. Krecke, Aditi S. Bapat, Tingyuan Yang, Michael W. Lopresti, Douglas G. Mashek, Ameeta Kelekar
Summary: The study revealed a novel role for PHLPP2 in targeting AMP-activated protein kinase (AMPK) to suppress the survival response of leukemia cells under glucose limitation. Silencing PHLPP2 prolonged the survival of leukemia cells by promoting AMPK-mediated fatty acid oxidation. This discovery could lead to better therapeutic strategies for both cancer and metabolic diseases.
CELL DEATH & DISEASE
(2021)
Review
Biochemistry & Molecular Biology
Brian M. Ortmann, James A. Nathan
Summary: Organisms have evolved oxygen-sensing mechanisms to adapt to oxygen availability; HIFs play a crucial role in oxygen-sensing in metazoans; Genetic studies have contributed significantly to our understanding of oxygen-sensing pathways.
Article
Cell Biology
Andreas M. Bapst, Thomas Knopfel, Karen A. Nolan, Faik Imeri, Claus D. Schuh, Andrew M. Hall, Jia Guo, Doerthe M. Katschinski, Roland H. Wenger
Summary: The kidney is the main source of erythropoietin (EPO) in circulating red blood cell production in adult mammals. In this study using a transgenic mouse model, multiple subtypes of renal EPO-producing (REP) cells were identified. Under nonpermissive conditions, REP-derived (REPD) cells stopped proliferating and acquired a stem cell-like state. These cells maintained the on-off nature of EPO expression observed in REP cells and exhibited myofibroblastic signaling. In vitro cultured REPD cells generated long nanotubes that aligned with blood vessels and increased in number under hypoxic conditions. Apart from pericytes, REPD cells readily differentiated into neuroglia but not adipogenic, chondrogenic, or osteogenic lineages.
JOURNAL OF CELLULAR PHYSIOLOGY
(2022)
Article
Cell Biology
Aline Jatho, Anke Zieseniss, Katja Brechtel-Curth, Jia Guo, Kai Oliver Boeker, Gabriela Salinas, Roland H. Wenger, Doerthe M. Katschinski
Summary: The anti-anemia drug roxadustat stabilizes HIFalpha and stimulates Epo synthesis by inhibiting the PHD enzymes. The study found that roxadustat treatment increased the number of Sca-1(+) mesenchymal cells in the kidneys, which exhibited characteristics of MSC-like cells and were capable of producing Epo under hypoxic conditions.
Article
Biochemistry & Molecular Biology
Redona Hafizi, Faik Imeri, Bisera Stepanovska Tanturovska, Roxana Manaila, Stephanie Schwalm, Sandra Trautmann, Roland H. Wenger, Josef Pfeilschifter, Andrea Huwiler
Summary: The study demonstrated that sphingolipids have diverse effects on Epo synthesis, with accumulation of intracellular Sph reducing Epo synthesis, while iS1P enhanced Epo synthesis through S1P(1+3) receptors. Selective inhibition of Sphk2 appears to be a promising approach to increase Epo synthesis and reduce anemia development in chronic kidney disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Multidisciplinary Sciences
Liang-Cui Chu, Pedro Arede, Wei Li, Erika C. Urdaneta, Ivayla Ivanova, Stuart W. McKellar, Jimi C. Wills, Theresa Frohlich, Alexander von Kriegsheim, Benedikt M. Beckmann, Sander Granneman
Summary: RNA-binding proteins play a crucial role in controlling gene expression. This study identifies hundreds of RNA-binding proteins in methicillin-resistant Staphylococcus aureus (MRSA) and demonstrates that a major transcription factor binds RNAs near intrinsic transcription terminators using its helix-turn-helix domain.
NATURE COMMUNICATIONS
(2022)
Article
Biology
Lewis Macdonald, Gillian C. Taylor, Jennifer Margaret Brisbane, Ersi Christodoulou, Lucy Scott, Alex von Kriegsheim, Janet Rossant, Bin Gu, Andrew J. Wood
Summary: Researchers have developed a genetic engineering method using CRISPR technology to efficiently degrade endogenous proteins in vivo, and found that degradation kinetics depend on the dosage of the protein, ligand, and substrate receptor. Applying this method to the study of key regulators of cell division, they discovered that these regulators are essential for cell division in precursor lymphocytes.
Article
Genetics & Heredity
Jennifer Lennon, Petra zur Lage, Alex von Kriegsheim, Andrew P. Jarman
Summary: Axonemal dynein motors are complex protein complexes that drive ciliary movement. The Drosophila homologues of DNAAF4 and DNAAF6, CG14921/Dnaaf4 and CG5048/Dnaaf6, are found to associate in a complex similar to R2TP and play a crucial role in dynein assembly during the development of motile cilia.
FRONTIERS IN GENETICS
(2022)
Editorial Material
Biochemistry & Molecular Biology
James A. Nathan
NATURE CHEMICAL BIOLOGY
(2023)
Editorial Material
Genetics & Heredity
James A. Nathan
Summary: A new study reveals that prolyl hydroxylation of histone H3 serves as a signal for the recruitment of KDM5A, leading to changes in H3K4me3 and gene expression. This hydroxylation is independent of the HIF hypoxia-sensing pathway and adds another layer of complexity to oxygen-sensitive chromatin modifications.
Article
Biochemistry & Molecular Biology
Stephen P. Burr, Florian Klimm, Angelos Glynos, Malwina Prater, Pamella Sendon, Pavel Nash, Christopher A. Powell, Marie-Lune Simard, Nina A. Bonekamp, Julia Charl, Hector Diaz, Lyuba V. Bozhilova, Yu Nie, Haixin Zhang, Michele Frison, Maria Falkenberg, Nick Jones, Michal Minczuk, James B. Stewart, Patrick F. Chinnery
Summary: Mitochondrial activity varies between organs, and lineage-specific expression profiles of essential mitochondrial genes emerge early in mouse development. Disrupting intra-mitochondrial protein synthesis with mtDNA mutations induces cell lineage-specific compensatory responses, including novel molecular pathways not previously associated with organellar maintenance. These compensatory pathways, regulated by transcription factors promoting organelle resilience, contribute to tissue specificity in mitochondrial diseases and may be potential targets for organ-directed treatments.
Article
Biochemistry & Molecular Biology
Bjort K. Kragesteen, Amir Giladi, Eyal David, Shahar Halevi, Laufey Geirsdottir, Olga M. Lempke, Baoguo Li, Andreas M. Bapst, Ken Xie, Yonatan Katzenelenbogen, Sophie L. Dahl, Fadi Sheban, Anna Gurevich-Shapiro, Mor Zada, Truong San Phan, Roberto Avellino, Shuang-Yin Wang, Oren Barboy, Shir Shlomi-Loubaton, Sandra Winning, Philipp P. Markwerth, Snir Dekalo, Hadas Keren-Shaul, Merav Kedmi, Martin Sikora, Joachim Fandrey, Thorfinn S. Korneliussen, Josef T. Prchal, Barak Rosenzweig, Vladimir Yutkin, Fernando Racimo, Eske Willerslev, Chamutal Gur, Roland H. Wenger, Ido Amit
Summary: Single-cell RNA and transposase-accessible chromatin (ATAC) sequencing in a mouse model identified a rare cell subset called Norn cells in kidney stroma as the major source of endocrine Epo production in mice, and this finding was confirmed in human kidney tissues. These findings provide new insights into EPO gene regulation and may lead to improved therapies for anemia.
Article
Multidisciplinary Sciences
Merve Kayhan, Judith Vouillamoz, Dayme Gonzalez Rodriguez, Milica Bugarski, Yasutaka Mitamura, Julia Gschwend, Christoph Schneider, Andrew Hall, David Legouis, Cezmi A. Akdis, Leary Peter, Hubert Rehrauer, Leslie Gewin, Roland H. Wenger, Stellor Nlandu Khodo
Summary: Excessive TGF-beta signaling and mitochondrial dysfunction contribute to the progression of chronic kidney disease (CKD). This study investigates the role of TGF-beta signaling in proximal tubule (PT) mitochondria dysfunction and inflammation in CKD. The findings suggest potential therapeutic targets to mitigate CKD progression.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Ana Martin-Vega, Laura Ruiz-Peinado, Rocio Garcia-Gomez, Ana Herrero, Dalia de la Fuente-Vivas, Swetha Parvathaneni, Ruben Caloto, Marta Morante, Alex von Kriegsheim, Xose R. Bustelo, David B. Sacks, Berta Casar, Piero Crespo
Summary: RAS-ERK pathway signals are regulated by scaffold proteins, and it is revealed that scaffold proteins can interact with each other and undergo phosphorylation reactions. The trans-phosphorylation process participates in KSR1-regulated adipogenesis and the cytotoxicity exhibited by KSR-directed inhibitors. This finding has implications in signaling and the design of scaffold protein-aimed therapeutics.
Article
Multidisciplinary Sciences
Willy Kuo, Diego Rossinelli, Georg Schulz, Roland H. Wenger, Simone Hieber, Bert Muller, Vartan Kurtcuoglu
Summary: The performance of machine learning algorithms in segmenting 3D biomedical images falls short of expectations compared to 2D photos. This is due to the lack of large, high-quality training datasets. The HR-Kidney dataset presented in this work provides a solution by offering a significantly larger dataset and can be used to further advance image processing, data augmentation, and machine learning research.
Article
Oncology
Aoife Nolan, Cinzia Raso, Walter Kolch, Alex von Kriegsheim, Kieran Wynne, David Matallanas
Summary: RAS proteins play a crucial role in cell signalling, regulating cell functions such as proliferation, differentiation, and death. Mutations in genes of this family, particularly KRAS, are common and were believed to constitutively activate KRAS. However, recent findings show that some mutants can switch between active and inactive states. This, along with the development of covalent KRASG12C inhibitors, has led to the emergence of KRAS inhibitors in clinical use. Despite this, resistance to targeted therapies remains a challenge, and effective treatments for other KRAS mutants are lacking. To overcome these hurdles and accelerate RAS targeting therapies, a comprehensive understanding of the molecular mechanisms underlying KRAS signalling networks and the differences in downstream signalling of KRAS mutants is needed. This study employed affinity purification mass-spectrometry proteomics to analyze the interactome of KRAS wild-type and three KRAS mutants. Through bioinformatic analysis and experimental validation, the researchers mapped the signalling network mediated by different KRAS proteins. The study also revealed novel crosstalk between KRAS and effector pathways, including AKT and JAK-STAT signalling modules.