Article
Biochemistry & Molecular Biology
Ya-Yun Chen, Xiang-Hong Ran, Run-Ze Ni, Dan Mu
Summary: TRIM28 is identified as a negative regulator of the RLR signaling pathway by targeting MAVS for proteasome-mediated degradation, which inhibits the production of type I interferons and proinflammatory cytokines induced by MAVS.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Lingmin Yuan, Zongyang Lv, Melanie J. Adams, Shaun K. Olsen
Summary: By determining the structure of a covalently trapped E1-E2-ubiquitin thioester mimetic, researchers identified two distinct conformations of the E1-E2-Ub complex which suggest the presence of an affinity switch mechanism facilitating thioester transfer.
NATURE COMMUNICATIONS
(2021)
Article
Multidisciplinary Sciences
Wenjing Yan, Yongwang Zhong, Xin Hu, Tuan Xu, Yinghua Zhang, Stephen Kales, Yanyan Qu, Daniel C. C. Talley, Bolormaa Baljinnyam, Christopher A. A. LeClair, Anton Simeonov, Brian M. M. Polster, Ruili Huang, Yihong Ye, Ganesha Rai, Mark J. J. Henderson, Dingyin Tao, Shengyun Fang
Summary: UBA1 is a key enzyme in the ubiquitination process, and enhancing its activity with auranofin, a drug approved for rheumatoid arthritis, could have therapeutic potential. Auranofin binds to UBA1 and enhances its interaction with E2 enzymes, promoting ubiquitination.
NATURE COMMUNICATIONS
(2023)
Article
Biology
Dawafuti Sherpa, Judith Mueller, Oezge Karayel, Peng Xu, Yu Yao, Jakub Chrustowicz, Karthik Gottemukkala, Christine Baumann, Annette Gross, Oliver Czarnecki, Wei Zhang, Jun Gu, Johan Nilvebrant, Sachdev S. Sidhu, Peter J. Murray, Matthias Mann, Mitchell J. Weiss, Brenda A. Schulman, Arno F. Alpi
Summary: This study measured the proteomic landscape of in vitro human erythropoiesis models and found dynamic differential expression of subunits of the CTLH E3 ubiquitin ligase complex, as well as changes in the protein abundance of UBE2H. Inactivation of CTLH E3 assemblies or UBE2H led to defects in erythroid progenitors, including accelerated maturation and inefficient enucleation. These findings suggest that dynamic changes in UBE2H-CTLH E2-E3 modules control the orderly progression of human erythropoiesis.
Article
Biochemistry & Molecular Biology
Xueer Wang, Honghai Zhang, Zhugui Shao, Wanxin Zhuang, Chao Sui, Feng Liu, Xiaorong Chen, Jinxiu Hou, Lingli Kong, Hansen Liu, Yi Zheng, Bingyu Liu, Tian Chen, Lei Zhang, Xinming Jia, Chengjiang Gao
Summary: The study revealed that TRIM31 regulates SYK activation through K27-linked polyubiquitination, promoting its translocation to the plasma membrane and binding with CLRs, while preventing interaction with SHP-1. Deficiency of Trim31 dampens SYK-mediated signaling, leading to impaired immune responses against Candida albicans infection.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2021)
Review
Biochemistry & Molecular Biology
David C. Hughes, Leslie M. Baehr, David S. Waddell, Adam P. Sharples, Sue C. Bodine
Summary: The development and prevalence of diseases associated with aging have a global health burden on society. One hallmark of aging is the loss of proteostasis, partly caused by alterations to the ubiquitin-proteasome system and lysosome-autophagy system, leading to impaired function and maintenance of mass in tissues such as skeletal muscle. In skeletal muscle, functional impairment occurs early in the aging process and depends on proteostatic mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Biochemistry & Molecular Biology
Jaeseok Lee, Youngjun Lee, Young Mee Jung, Ju Hyun Park, Hyuk Sang Yoo, Jongmin Park
Summary: Target protein degradation is an emerging strategy for therapeutics discovery. Proteolysis-targeting chimera (PROTAC) utilizes cellular ubiquitin-dependent proteolysis system to efficiently degrade a protein of interest. However, the current PROTAC technology is limited by the cell type specific expression of E3 ligases and resistance to CRBN or VHL ligands. Therefore, the discovery of new E3 ligase ligands is crucial for improving PROTAC technology.
Article
Biochemistry & Molecular Biology
Kaeli A. Welsh, Derek L. Bolhuis, Anneroos E. Nederstigt, Joshua Boyer, Brenda R. S. Temple, Thomas Bonacci, Li Gu, Alban Ordureau, J. Wade Harper, Joshua P. Steimel, Qi Zhang, Michael J. Emanuele, Joseph S. Harrison, Nicholas G. Brown
Summary: Polyubiquitination mediated by E2 and E3 enzymes is essential for cell cycle control, epigenetic regulation, and development. The helix-turn-helix (HTH) motif of the UBC has been shown to regulate the intrinsic polyubiquitination activity in different E2s, with distinct functions observed in UBE2S and UBE2R2. The repurposing of the E2(HTH) motif in these proteins suggests a new mechanism for modulating ubiquitin transfer and highlights the potential for additional regulation in E2-E3-mediated polyubiquitination.
Article
Multidisciplinary Sciences
Yawei Ru, Xiaojie Yan, Bing Zhang, Lili Song, Qiqi Feng, Chen Ye, Zhili Zhou, Zhenzhen Yang, Yao Li, Zhenjian Zhang, Qianqian Li, Wenyi Mi, Cheng Dong
Summary: In this study, a new C-degron pathway, called the Gln/C-degron pathway, was discovered. The B30.2 domain of TRIM7 mediates the recognition of proteins with a C-terminal glutamine. The C-terminal residues of the substrate play a crucial role in C-degron recognition.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Lydia Qian, Laura J. Sharpe, Akira Gokool, Irina Voineagu, Andrew J. Brown
Summary: Circular RNAs (circRNAs) have various functions, and the MARCHF6 circRNA plays a crucial role in cholesterol homeostasis.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2023)
Article
Cell Biology
Yi-Ting Wang, Ting-Yu Liu, Chia-Hsing Shen, Shu-Yu Lin, Chin-Chun Hung, Li-Chung Hsu, Guang-Chao Chen
Summary: Excessive generation and accumulation of highly reactive oxidizing molecules can lead to oxidative stress and damage to cellular components. Autophagy, through degradation and recycling of damaged components, plays a role in reducing oxidative damage and maintaining redox homeostasis. This study reveals the coordination between TRAF6 E3 ubiquitin ligase and A20 deubiquitinase in regulating ATG9A ubiquitination and autophagy activation in response to oxidative stress. The findings shed light on the importance of K48/K63-linked ubiquitination of ATG9A in the regulation of oxidative stress-induced autophagy.
Article
Chemistry, Multidisciplinary
Lu-Jun Liang, Guo-Chao Chu, Qian Qu, Chong Zuo, Junxiong Mao, Qingyun Zheng, Jingnan Chen, Xianbin Meng, Yangwode Jing, Haiteng Deng, Yi-Ming Li, Lei Liu
Summary: This study describes a new total chemical synthesis approach for constructing a structurally new activity-based E2-Ub probe, which covalently captures the catalytic site of Cys-dependent E3 ligases. Chemical cross-linking coupled with mass spectrometry demonstrated the utility of this new probe in structural analysis of intermediates formed during thiol transfer processes. The study exemplifies the utility of chemical protein synthesis in developing protein probes for biological studies.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biochemistry & Molecular Biology
Yulemi Gonzalez Quesada, Luc DesGroseillers
Summary: This study investigates the degradation mechanism of RNA-binding protein STAU1 in cancer cells. The research reveals that STAU1 degradation is related to the FPL-motif protein family and inflammation-related protein MAP4K1. Through experiments, it is confirmed that TRIM25 is the E3 ubiquitin ligase responsible for the degradation of STAU1 and MAP4K1. These findings are significant for further exploration of the inflammation mechanisms associated with cancer.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Lu Gong, Samuel Bates, Yujun Li, Xin Lin, Wenyi Wei, Xiaobo Zhou
Summary: Research found that SNPs within the FAM13A gene are significantly associated with chronic obstructive pulmonary disease and lung function. After treatment with cigarette smoke extract, FAM13A protein is phosphorylated at the serine 312 residue by AKT kinase and recognized by the CULLIN4A/DCAF1 E3 ligase complex, leading to its ubiquitination-mediated degradation. Additionally, AKT activation also leads to downregulation of FAM13A protein levels in mice with influenza or naphthalene-induced lung injury. Functionally, reduced FAM13A protein levels accelerate epithelial cell proliferation in murine lungs during the recovery phase after injury.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Jianzhong Huang, Xiaoqiu Wu, Zhiyong Gao
Summary: Ubiquitination plays a crucial role in regulating the turnover of nucleotide-binding site and leucine-rich repeat receptors (NLRs). BOI, a RING-type E3 ligase, has been found to interact with and ubiquitinate L5, leading to its proteasomal degradation outside the nucleus. BOI and its homologs, BRG1 and BRG3, function redundantly to negatively regulate the protein level of L5, demonstrating their multiple targets and subcellular functions.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
Emma I. Kane, Donald E. Spratt
Summary: Ankyrin repeat (AR) domains are the most common repetitive structure in eukaryotic proteins, mediating specific protein-protein interactions and recognizing a variety of intracellular substrates. Proteins with AR domains play crucial roles in biological processes and their dysfunction is linked to neurological diseases and disorders. Understanding the structure and mechanism of key AR-containing proteins can provide insights into how they support ubiquitylation and subsequent signaling pathways.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Qing Yu, Yi Sun
Summary: Cullin-RING E3 ligases (CRLs) are the largest family of E3 ubiquitin ligases, responsible for about 20% of protein degradation by the ubiquitin-proteasome system. Gossypol, a natural product extracted from cottonseeds, was identified as a potent inhibitor of cullin-1 and cullin-5 neddylation, leading to the accumulation of MCL-1 and NOXA, substrates of CRL1 and CRL5, respectively. The combination of gossypol and an MCL-1 inhibitor showed synergistic anti-proliferative effects in multiple human cancer cell lines, suggesting a promising strategy for anti-cancer therapy.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2021)
Editorial Material
Cell Biology
Chan Lee, Michael Overholtzer
Summary: Lysosomes play a crucial role in cellular quality control mechanisms, with LC3 lipidation promoting microautophagy formation. LC3 lipidation functions in response to metabolic stress, allowing cells to adapt to changing metabolic conditions through selective turnover of lysosomal membrane.
Review
Oncology
Nicholas A. Mathieu, Rafael H. Levin, Donald E. Spratt
Summary: Cellular homeostasis is regulated by gene expression controlling protein translation, localization, and termination. Mutations caused by environmental and biological factors can lead to protein malfunction and malignant transformations. The tumor suppressor protein p53 undergoes numerous posttranslational modifications and plays a role in apoptosis, transcription, and DNA damage response. Irregular interactions between HECT E3 ubiquitin ligases and p53 can induce tumorigenesis.
FRONTIERS IN ONCOLOGY
(2021)
Review
Virology
Nicholas A. Mathieu, Ermela Paparisto, Stephen D. Barr, Donald E. Spratt
Summary: ISG15 is a crucial immunoprotein that plays a significant role in antiviral immunity, with HERC5 regulating its signaling pathway to promote the ISGylation of viral proteins in response to various viral infections.
Article
Pharmacology & Pharmacy
Yanan Li, Chaorong Wang, Tiantian Xu, Peichen Pan, Qing Yu, Lei Xu, Xiufang Xiong, Tingjun Hou, Sunliang Cui, Yi Sun
Summary: A small molecule compound HA-1141 was discovered to inhibit neddylation and induce ER stress, leading to growth suppression of cancer cells.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Biochemistry & Molecular Biology
Fengwu Zhang, Yongchao Zhao, Yi Sun
Summary: USP2 was identified as a new deubiquitylase that stabilizes SKP2 protein by disrupting its interaction with substrates, thereby affecting cell growth regulation. Inactivation of USP2 can shorten SKP2 protein half-life and enhance its ubiquitylation and degradation, but surprisingly, USP2-stabilized SKP2 does not destabilize its substrates p21 and p27. Knockdown or inhibition of USP2 can partially mediate growth suppression through modulation of SKP2 and its substrates.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Meeting Abstract
Biochemistry & Molecular Biology
Emma I. Kane, Kayla Rich, Steven Beasley, Donald E. Spratt
Article
Multidisciplinary Sciences
Di Wu, Haomin Li, Mingwei Liu, Jun Qin, Yi Sun
Summary: This study reveals that the absence of Rbx1, a component of Cullin-RING ligases, in regulatory T cells leads to a severe inflammatory disease. The Ube2m-Rbx1 axis is specifically required for intrinsic regulatory processes in Treg cells.
NATURE COMMUNICATIONS
(2022)
Article
Cell Biology
Shizhen Zhang, Xiahong You, Tiantian Xu, Qian Chen, Hua Li, Longyu Dou, Yilun Sun, Xiufang Xiong, Morgan A. Meredith, Yi Sun
Summary: In this study, it was found that MLN4924 increased the levels of PD-L1 mRNA and protein, which was largely independent of neddylation inactivation. The mechanism involved the activation of ERK and JNK signals, leading to AP-1 activation. MLN4924 attenuated T cell killing and this effect could be abrogated by MEK inhibitor or anti-PD-L1 antibody. Combination of MLN4924 with MEK inhibitor or anti-PD-L1 antibody enhanced the suppression of tumor growth in an in vivo xenograft tumor model.
CELL DEATH & DISEASE
(2022)
Editorial Material
Biochemistry & Molecular Biology
Di Wu, Yi Sun
Summary: Neddylation, a ubiquitylation-like post-translational modification, is essential for the maintenance of Treg functionality. The Ube2m-Rbx1 pair of neddylation enzymes plays a crucial role, while the Ube2f-Sag pair has minimal or no effect on Treg cells. Understanding the regulation of neddylation-CRLs axis in immune cells can provide insights into potential therapeutic targets for human cancers and autoimmune diseases.
Review
Biochemistry & Molecular Biology
ZiWei Li, Gary S. Shaw
Summary: Cell membrane repair is a crucial process for cell survival and integrity, which involves multiple mechanisms such as exocytosis, endocytosis, patching, and shedding. Calcium-sensor proteins, including synaptotagmins, dysferlin, S100 proteins, and annexins, play a regulatory or participatory role in membrane repair. Dysfunctions or genetic alterations in these proteins can lead to diseases such as muscular dystrophy and heart disease. This review focuses on the role of key calcium-sensor proteins in membrane repair.
BIOSCIENCE REPORTS
(2023)
Article
Cell Biology
Mingjia Tan, Yu Chang, Xiaoqiang Liu, Hua Li, Zaiming Tang, Mukesh K. Nyati, Yi Sun
Summary: This study investigates the role of Sag-Shoc2 crosstalk in pancreatic tumorigenesis. Deletion of Sag promotes tumor development, while deletion of Shoc2 inhibits this process. Sag targets Shoc2 for degradation, affecting the Mapk and mTorc1 pathways.
Article
Biochemistry & Molecular Biology
Xue Liang, Jiping Yao, Danrui Cui, Weiyang Zheng, Yanning Liu, Guohua Lou, Bingjue Ye, Liyan Shui, Yi Sun, Yongchao Zhao, Min Zheng
Summary: This study investigated the dysregulation of TRAF2 in liver cancer and its biological function, aiming to validate TRAF2 as a promising therapeutic target for liver cancer.
CELL DEATH AND DIFFERENTIATION
(2023)
Article
Oncology
Shizhen Zhang, Yi Sun
Summary: CRL and APC/C, two RING-finger-type E3 ligases, regulate the cell cycle through negative crosstalk, ensuring the orderly progression of the cell cycle.
MOLECULAR & CELLULAR ONCOLOGY
(2021)