Review
Biochemistry & Molecular Biology
Rui Zhang, Shaoqing Shi
Summary: HECT-type E3 ubiquitin ligases play a vital role in controlling protein function and stability, and members of the NEDD4 family have critical roles in dysregulation of autophagy in cancer cells. This review focuses on the role of NEDD4 E3 ligases in defective autophagy in cancer cells, discussing their function, substrates, and signaling pathways, providing a basis for cancer treatment through modulation of these ligases.
MOLECULAR MEDICINE
(2023)
Article
Biology
Lu Zhu, Qing Zhang, Ciro D. Cordeiro, Sudeep Banjade, Richa Sardana, Yuxin Mao, Scott D. Emr
Summary: The study reveals a novel ubiquitination modification implemented by Rsp5 adaptor proteins, which controls the recruitment and activity of Rsp5 to facilitate the turnover of membrane proteins.
Article
Biochemistry & Molecular Biology
Amanda B. Chai, Richard Callaghan, Ingrid C. Gelissen
Summary: The study demonstrates that NEDD4-1 regulates the expression and activity of P-gp, thereby facilitating the clearance of Aβ peptides from the brain. This finding offers a potential approach for the treatment of Alzheimer's disease.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Cell Biology
Emanuela Senatore, Rosa Iannucci, Francesco Chiuso, Rossella Delle Donne, Laura Rinaldi, Antonio Feliciello
Summary: Primary cilia are microtubule-based sensory organelles that receive and transmit external signals to control cell growth, differentiation, and development. The formation and disassembly of primary cilia are finely regulated during the cell cycle. The ubiquitin-proteasome system and autophagy machinery play essential roles in cilia dynamics.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Physiology
Xinxin Lu, Haiqi Xu, Jiaqi Xu, Saien Lu, Shilong You, Xinyue Huang, Naijin Zhang, Lijun Zhang
Summary: This review summarizes the functions of NEDD4 family members in DNA damage response and discusses their roles in the cascade reactions induced by DNA damage.
FRONTIERS IN PHYSIOLOGY
(2022)
Article
Genetics & Heredity
James A. Conway, Grant Kinsman, Edgar R. Kramer
Summary: Parkinson's disease is a neurodegenerative disease with unclear molecular pathologies. Enhancing the clearance of alpha-synuclein, a proposed causative protein, is a central idea for PD research. NEDD4 ligases have been shown to influence the degradation of alpha-synuclein and may be potential therapeutic targets for PD. Understanding the expression and function of NEDD4 ligases in the brain is crucial for uncovering the mechanisms of PD.
Article
Biochemistry & Molecular Biology
Kai Li, Yi Niu, Yichuan Yuan, Jiliang Qiu, Yunxing Shi, Chengrui Zhong, Zhiyu Qiu, Keren Li, Zhu Lin, Zhenkun Huang, Chao Zhang, Dinglan Zuo, Wei He, Yunfei Yuan, Binkui Li
Summary: Insufficient thermal ablation can promote the progression of hepatocellular carcinoma (HCC) and upregulate the E3 ligase Nedd4. Nedd4 enhances the TGF-beta signal transduction, promoting tumor growth and metastasis. High Nedd4 expression correlates with aggressive tumor phenotypes and poor prognosis in HCC patients.
Article
Biology
Aiqin Sun, Jun Zhu, Song Xia, Yanling Li, Tiantian Wu, Genbao Shao, Wannian Yang, Qiong Lin
Summary: The study revealed that NEDD4 interacts with MEKK5 through a conserved WW3 domain, but MEKK5 is not a ubiquitination substrate of NEDD4 and instead negatively regulates NEDD4-mediated ubiquitination. Overexpression of MEKK5 significantly reduces NEDD4-promoted lung cancer cell migration.
Article
Biochemistry & Molecular Biology
Hao-Yu Chuang, Li-Yun Hsu, Chih-Ming Pan, Narpati Wesa Pikatan, Vijesh Kumar Yadav, Iat-Hang Fong, Chao-Hsuan Chen, Chi-Tai Yeh, Shao-Chih Chiu
Summary: The overexpression of NEDD4-1 in GBM and TMZ-resistant cells is associated with oncogenicity, tumorigenesis, and chemoresistance. Mechanistically, NEDD4-1 mediates the degradation of PTEN and upregulation of the AKT/NRF2/HO-1 signaling pathway, leading to increased defense against reactive oxygen species and higher resistance against TMZ treatment. Targeting this regulatory axis may help eliminate TMZ-resistant glioblastoma.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Oncology
Liangzi Cao, Hao Li, Xiaofang Liu, Yubang Wang, Bowen Zheng, Chengzhong Xing, Naijin Zhang, Jingwei Liu
Summary: This study investigated the molecular alterations and clinical relevance of NEDD4 E3 ligase family genes in 33 cancer types. The findings revealed increased expression of NEDD4 members in pancreatic cancer and decreased expression in thyroid cancer. NEDD4 family genes exhibited a range of mutation frequencies, with HECW1 and HECW2 showing relatively high mutation rates. Breast cancer presented with a high frequency of NEDD4 copy number amplification. Additionally, NEDD4 family members were involved in various pathways such as p53, Akt, apoptosis, and autophagy, and their expression correlated with the survival of cancer patients.
Correction
Biochemistry & Molecular Biology
Daphne E. Lodes, Jiuhe Zhu, Nien-Pei Tsai
Summary: E3 ubiquitin ligase Nedd4-2 exerts neuroprotective effects during endoplasmic reticulum stress.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Orsolya Bilkei-Gorzo, Tiaan Heunis, Jose Luis Marin-Rubio, Francesca Romana Cianfanelli, Benjamin Bernard Armando Raymond, Joseph Inns, Daniela Fabrikova, Julien Peltier, Fiona Oakley, Ralf Schmid, Anetta Hartlova, Matthias Trost
Summary: This study reveals the importance of phagosomal ubiquitylation and the E3 ubiquitin ligase RNF115 in regulating innate immune functions during bacterial infections.
Article
Chemistry, Medicinal
Adam G. Bond, Conner Craigon, Kwok-Ho Chan, Andrea Testa, Athanasios Karapetsas, Rotimi Fasimoye, Thomas Macartney, J. Julian Blow, Dario R. Alessi, Alessio Ciulli
Summary: This study describes the design and development of a new protein degradation system utilizing a variant of the Brd4 bromodomain as a degradation tag. The system effectively degrades BromoTagged proteins in a fast, selective manner, showing favorable pharmacokinetic profile in mice. This system expands the arsenal of chemical genetic degradation tools for manipulating protein levels and exploring therapeutic potential in cells and in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Martin P. Schwalm, Lena M. Berger, Maximilian N. Meuter, James D. Vasta, Cesear R. Corona, Sandra Roehm, Benedict-Tilman Berger, Frederic Farges, Sebastian M. Beinert, Franziska Preuss, Viktoria Morasch, Vladimir V. Rogov, Sebastian Mathea, Krishna Saxena, Matthew B. Robers, Susanne Mueller, Stefan Knapp
Summary: E3 ligases play a crucial role in regulating protein homeostasis by recruiting substrate proteins to the proteasomal degradation machinery. Recent research has focused on the Baculovirus IAP Repeat (BIR) family of E3 ligases, which contain a structurally conserved but diverse protein interaction domain. The Inhibitors of Apoptosis (IAP) family, which typically have three BIR domains, are promising drug targets. However, there is currently a lack of assay tools to evaluate the selectivity of inhibitors in this target area.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2022)
Review
Immunology
Haoran Cui, Yaxian Zhang, Leiliang Zhang
Summary: Poxviruses have evolved various mechanisms to evade innate immunity, some of which involve poxvirus-encoded E3 ubiquitin ligases and adaptor proteins. These proteins can be categorized into five groups based on their functional domains and ubiquitin transfer mechanisms. Most known substrates of poxvirus E3 ubiquitin ligases are components of the innate immune system. Current research progress provides mechanistic insights into the interaction between these viruses and their hosts.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Daniel Horn-Ghetko, Brenda A. Schulman
Summary: Recent advancements in the identification and mechanistic characterization of ubiquitin ligases in eukaryotes have revealed novel mechanisms and expanded the types of substrates modified by these ligases. Utilization of activity-based chemical probes and cryo-EM has played a significant role in these discoveries.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Christine R. Langlois, Viola Beier, Ozge Karayel, Jakub Chrustowicz, Dawafuti Sherpa, Matthias Mann, Brenda A. Schulman
Summary: Cells remodel their proteomes to adjust to environmental metabolism demands. The GID E3 ligase regulates the transition from gluconeogenesis to glycolysis, while the Gid10 substrate receptor plays a role in responding to changes in temperature, osmolarity, and nutrient availability, regulating plasma membrane quality control.
Article
Cell Biology
Tzu-Jing Yang, Tian-Neng Li, Rih-Sheng Huang, Max Yu-Chen Pan, Shu-Yu Lin, Steven Lin, Kuen-Phon Wu, Lily Hui-Ching Wang, Shang-Te Danny Hsu
Summary: The subcellular localization of BAP1 is crucial for its tumor suppressor activity. This study reveals that transportin-1 (TNPO1) plays a key role in the nuclear import of BAP1 by binding to its unique nuclear localization signal (PY-NLS) motif. TNPO1 also dissociates the dimeric structure of BAP1 and prevents its monoubiquitination to counteract the cytosolic retention by UBE2O.
JOURNAL OF CELL BIOLOGY
(2022)
Review
Cell Biology
Ivan Dikic, Brenda A. Schulman
Summary: Recent studies have advanced our understanding of ubiquitylation, revealing unconventional ubiquitylation mechanisms used by pathogens to promote infection. Structural studies have shown that ubiquitin functions involve complex multivalent interactions that regulate transcription or protein degradation. Furthermore, these interactions can induce conformational changes and regulate protein degradation or transcription. These newly discovered mechanisms provide potential opportunities for innovative therapeutic interventions for diseases such as cancer and infectious diseases.
NATURE REVIEWS MOLECULAR CELL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Kheewoong Baek, Daniel C. Scott, Lukas T. Henneberg, Moeko T. King, Matthias Mann, Brenda A. Schulman
Summary: Cells respond to environmental cues by remodeling their inventories of multiprotein complexes. Cellular repertoires of SCF ubiquitin ligase complexes require CAND1 to distribute the limiting CUL1 subunit across different F box proteins. The molecular basis for systemwide multiprotein complex assembly remains unknown.
Article
Biochemistry & Molecular Biology
Felix Kraus, Ellen A. Goodall, Ian R. Smith, Yizhi Jiang, Julia C. Paoli, Frank Adolf, Jiuchun Zhang, Joao A. Paulo, Brenda A. Schulman, J. Wade Harper
Summary: Protein kinase PINK1 and ubiquitin ligase Parkin promote removal of damaged mitochondria through a feed-forward mechanism involving ubiquitin phosphorylation, Parkin activation, and ubiquitylation of mitochondrial outer membrane proteins. However, the involvement of FBXO7 in Parkin-dependent mitophagy is not supported by the findings of this study. FBXO7(-/-) cells showed no defects in various aspects of mitophagy, suggesting that additional studies are needed to understand how FBXO7 mutations contribute to Parkinsonian-pyramidal syndrome.
Article
Biochemistry & Molecular Biology
Meng-Ru Ho, Yi-Ming Wu, Yen-Chen Lu, Tzu-Ping Ko, Kuen-Phon Wu
Summary: In this study, a cryo-electron microscopy (cryo-EM) structure of a 723-amino acid protein called malate synthase G (MSG) from Escherichia coli was determined at a resolution of 2.9 A. The cryo-EM structure of this 82-kDa protein was found to be similar to structures resolved by X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, with no distinguishable differences. The study also revealed consistent conformational flexibilities among different experimental approaches, particularly in the alpha/beta domain. Additionally, differences in sidechain rotations of certain residues involved in hosting the cofactor acetyl-CoA and substrate were observed between the cryo-EM apo-form and complex crystal structures. These findings demonstrate that cryo-EM can be used to determine the structures and conformational heterogeneity of sub-100 kDa biomolecules with a quality comparable to X-ray crystallography and NMR spectroscopy.
JOURNAL OF STRUCTURAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Meijing Li, Ishita Tripathi-Giesgen, Brenda A. Schulman, Wolfgang Baumeister, Florian Wilfling
Summary: Selective macroautophagy is a process in which cytosolic material is enclosed in a double membrane organelle and transported to a lytic compartment for degradation. This study used cryo-electron tomography to observe the formation of phagophores around damaged Salmonella-containing vacuoles (SCVs). Host cells generated multiple phagophores at the site of SCVs and established contact with the endoplasmic reticulum for membrane formation and expansion.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Multidisciplinary Sciences
Yu-Hsuan Chen, Han-Hsiun Chen, Won-Jing Wang, Hsin-Yi Chen, Wei-Syun Huang, Chien-Han Kao, Sin-Rong Lee, Nai Yang Yeat, Ruei-Liang Yan, Shu-Jou Chan, Kuen-Phon Wu, Ruey-Hwa Chen
Summary: Activation of tumor-intrinsic innate immunity is crucial for improving immunotherapy. The deubiquitinating enzyme TRABID is found to play a suppressive role in anti-tumor immunity by regulating mitotic cell division and activating the cGAS/STING pathway. TRABID inhibition induces micronuclei and protects cGAS from autophagy, thus promoting anti-tumor immune responses.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Ta Hung, Yun-Jung Hsieh, Wei-Lin Lu, Amy Keating, Kuen-Phon Wu, Chia-en A. Chang
Summary: This study uses computational modeling to reveal the essential residue interaction network and dihedral angle correlations in protein-protein recognition. By mutating residues with highly correlated dynamic motion within the interaction network, the study shows an effective approach to optimize protein-protein interactions and create tight and selective protein binders.
JOURNAL OF MOLECULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Lukas T. Henneberg, Jaspal Singh, David M. Duda, Kheewoong Baek, David Yanishevski, Peter J. Murray, Matthias Mann, Sachdev S. Sidhu, Brenda A. Schulman
Summary: Researchers have developed conformation-specific antibodies to probe the NEDD8-activated cullin-RING ubiquitin E3 ligase networks in mammalian cells in response to extracellular stimuli, metabolic signals, and degrader drugs.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Yuan-Chao Lou, Hsuan-Yu Huang, Hsin-Hong Yeh, Wei-Hung Chiang, Chinpan Chen, Kuen-Phon Wu
Summary: This study reports the structure of a bacterial PmrA-dependent transcription activation complex, which reveals that RNAPH interacts with the C-terminal DNA-binding domain of PmrA via electrostatic interactions and reorients the DBD, resulting in a dynamic TAC conformation. In vivo assays show that substitution of the DNA-recognition residue eliminates its transcriptional activity, while variants with altered RNAPH-interacting residues result in enhanced transcriptional activity. These findings suggest the importance of both PmrA recognition-induced DNA distortion and promoter escape in its transcriptional activation.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Cell Biology
Shaifali Singh, Nai Yang Yeat, Ya-Ting Wang, Shu-Yu Lin, I-Ying Kuo, Kuen-Phon Wu, Won-Jing Wang, Wen-Ching Wang, Wu-Chou Su, Yi-Ching Wang, Ruey-Hwa Chen
Summary: WDR4/PTPN23 axis plays a central role in the trafficking of EGFR and c-MET in non-small cell lung cancer (NSCLC). WDR4-mediated PTPN23 ubiquitination inhibits lysosome trafficking and degradation, sustaining EGFR and c-MET signaling and promoting NSCLC proliferation, migration, and metastasis. Clinical studies show that low expression of PTPN23 is associated with high expression of WDR4 and poor prognosis in lung cancer. Targeting WDR4-mediated PTPN23 ubiquitination may be a potential therapeutic strategy for EGFR TKI-resistant NSCLC.
CELL DEATH & DISEASE
(2023)
Article
Biochemical Research Methods
Hsi-Wen Kao, Wei-Lin Lu, Meng-Ru Ho, Yu-Fong Lin, Yun-Jung Hsieh, Tzu-Ping Ko, Shang-Te Danny Hsu, Kuen-Phon Wu
Summary: We used ProteinMPNN, a deep learning tool, to redesign ubiquitin (Ub) as a specific and functionally stimulating/enhancing binder of the Rsp5 E3 ligase. We generated 20 extensively mutated Ub variants (UbVs) named R1 to R20, which displayed well-folded structures and high thermal stabilities. These UbVs can form stable complexes with Rsp5, as predicted by AlphaFold2. Three of the UbVs showed low micromolar affinity to Rsp5, with R4 and R12 effectively enhancing Rsp5 activity six folds. AlphaFold2 predicts that R4 and R12 bind to Rsp5's exosite in the same manner as the Rsp5-Ub template, thereby allosterically activating Rsp5-Ub thioester formation. Thus, we present a virtual solution for rapidly and cost-effectively designing functional modulators of Ub-related enzymes.
ACS SYNTHETIC BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Iona Wallace, Kheewoong Baek, J. Rajan Prabu, Ronnald Vollrath, Susanne von Gronau, Brenda A. Schulman, Kirby N. Swatek
Summary: This study presents a Cryo-EM structure of the ISG15 complex with its E1 and E2 enzymes, providing insights into the specificity determinants of this pathway.
NATURE COMMUNICATIONS
(2023)