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ubiquitin ligase

Jacint G Sanchez, Konstantin M J Sparrer, Cindy Chiang, Rebecca A Reis, Jessica J Chiang, Matthew A Zurenski, Yueping Wan, Michaela U Gack, Owen Pornillos
TRIM25 is a multi-domain, RING-type E3 ubiquitin ligase of the tripartite motif family that has important roles in multiple RNA-dependent processes. In particular, TRIM25 functions as an effector of RIG-I and ZAP, which are innate immune sensors that recognize viral RNA and induce ubiquitin-dependent anti-viral response mechanisms. TRIM25 is reported to also bind RNA, but the molecular details of this interaction or its relevance to anti-viral defense have not been elucidated. Here, we characterize the RNA-binding activity of TRIM25 and find that the protein binds both single-stranded and double-stranded RNA...
October 17, 2018: Journal of Molecular Biology
Guillem Lambies, Martina Miceli, Catalina Martínez-Guillamon, Ruben Olivera-Salguero, Raúl Peña, Carolina-Paola Frías, Irene Calderón, Boyko S Atanassov, Sharon Y R Dent, Joaquin Arribas, Antonio García de Herreros, Víctor M Díaz
In cancer cells, epithelial-to-mesenchymal transition (EMT) is controlled by Snail1, a transcriptional factor also required for the activation of cancer-associated fibroblasts (CAF). Snail1 is short-lived in normal epithelial cells as a consequence of its coordinated and continuous ubiquitination by several F-box specific E3 ligases, but its degradation is prevented in cancer cells and in activated fibroblasts. Here we performed an siRNA screen and identified USP27X as a deubiquitinase that increases Snail1 stability...
October 19, 2018: Cancer Research
Wei Wan, Zhiyuan You, Li Zhou, Yinfeng Xu, Chao Peng, Tianhua Zhou, Cong Yi, Yin Shi, Wei Liu
mTORC1, the major homeostatic sensor and responder, regulates cell catabolism mainly by targeting autophagy. Here, we show that mTORC1 directly controls autophagosome formation via phosphorylation of WIPI2, a critical protein in isolation membrane growth and elongation. mTORC1 phosphorylates Ser395 of WIPI2, directing WIPI2 to interact specifically with the E3 ubiquitin ligase HUWE1 for ubiquitination and proteasomal degradation. Physiological or pharmacological inhibition of mTORC1 in cells promotes WIPI2 stabilization, autophagosome formation, and autophagic degradation...
October 18, 2018: Molecular Cell
Youngjo Kim, Hyung-Jun Kim, Sun Joo Cha, Hyun-Jun Choi, Hayoung Kim, Sanghyun Lee, Yu-Mi Jeon, Mihye Lee, Seongsoo Lee, Kiyoung Kim
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder that is characterized pathologically by the loss of motor neurons. Mutations in the TAF15 gene have been implicated in the pathogenesis of ALS. TATA-binding protein associated factor 15 (TAF15) accumulates as cytoplasmic aggregates in neuronal cells, the clearance of which may be a therapeutic strategy for ALS. However, the identification of a novel regulator for protection against a TAF15-induced proteinopathy and the exact pathogenic mechanism of TAF15-induced neurodegeneration remain to be elucidated...
September 22, 2018: Neurobiology of Aging
J Kanungo, M T Goswami, H C Pant
Notch signalling is critical for the development of the nervous system. In the zebrafish mindbomb mutants, disruption of E3 ubiquitin ligase activity inhibits Notch signalling. In these mutant embryos, precocious development of primary neurons leading to depletion of neural progenitor cells results in a neurogenic phenotype characterized by defects in neural patterning and brain development. Cyclin-dependent kinase 5 (Cdk5), a predominant neuronal kinase, is involved in a variety of essential functions of the nervous system...
2018: Folia Biologica (Praha)
Thomas Briston, Jenna M Stephen, Luke W Thomas, Cinzia Esposito, Yuen-Li Chung, Saiful E Syafruddin, Mark Turmaine, Lucas A Maddalena, Basma Greef, Gyorgy Szabadkai, Patrick H Maxwell, Sakari Vanharanta, Margaret Ashcroft
Dysregulated mitochondrial function is associated with the pathology of a wide range of diseases including renal disease and cancer. Thus, investigating regulators of mitochondrial function is of particular interest. Previous work has shown that the von Hippel-Lindau tumor suppressor protein (pVHL) regulates mitochondrial biogenesis and respiratory chain function. pVHL is best known as an E3-ubiquitin ligase for the α-subunit of the hypoxia inducible factor (HIF) family of dimeric transcription factors. In normoxia, pVHL recognizes and binds hydroxylated HIF-α (HIF-1α and HIF-2α), targeting it for ubiquitination and proteasomal degradation...
2018: Frontiers in Oncology
Hui-Huang Lai, Li-Jyuan Lin, Liang-Yi Hung, Pai-Sheng Chen
Colorectal cancer (CRC) is a major health problem due to its high mortality rate. The incidence of CRC is increasing in young individuals. Oxaliplatin (OXA) is an approved third-generation drug and is used for first-line chemotherapy in CRC. Although current standard chemotherapy improves the overall survival of CRC patients, an increasing number of reports of OXA resistance in CRC therapy indicates that resistance has become an urgent problem in clinical applications. Dicer is a critical enzyme involved in miRNA maturation...
October 16, 2018: Biochemical and Biophysical Research Communications
Jung-Gyu Lee, Hyung-Seop Youn, Jung Youn Kang, Sam-Yong Park, Akinori Kidera, Yung Joon Yoo, Soo Hyun Eom
Ubiquitin-conjugating enzymes (E2) form thioester bonds with ubiquitin (Ub), which are subsequently transferred to target proteins for cellular progress. Ube2K/E2-25K (a class II E2 enzyme) contains a C-terminal ubiquitin-associated (UBA) domain that has been suggested to control ubiquitin recognition, dimerization, or poly-ubiquitin chain formation. Ube2K is a special E2 because it synthesizes K48-linked poly-ubiquitin chains without E3 ubiquitin ligase. We found that a novel interaction between the acceptor di-Ub (Ub2 ) and the auxiliary Ube2K promotes the discharging reaction and production of tri-Ub (Ub3 ), probably by guiding and positioning the K48 (in the distal Ub) of the acceptor Ub2 in the active site...
October 16, 2018: Biochemical and Biophysical Research Communications
Brandy Verhalen, Susan Arnold, Berge A Minassian
Lafora's disease is a neurodegenerative disorder caused by recessive loss-of-function mutations in the EPM2A (laforin glycogen phosphatase) or EPM2B (malin E3 ubiquitin ligase) genes. Neuropathology is characterized by malformed precipitated glycogen aggregates termed Lafora bodies. Asymptomatic until adolescence, patients undergo first insidious then rapid progressive myoclonus epilepsy toward a vegetative state and death within a decade. Laforin and malin interact to regulate glycogen phosphorylation and chain length pattern, the latter critical to glycogen's solubility...
October 18, 2018: Neuropediatrics
April N Meyer, Leandro H Gallo, Juyeon Ko, Guillermo Cardenas, Katelyn N Nelson, Asma Siari, Alexandre R Campos, Thomas C Whisenant, Daniel J Donoghue
Mutations at position K171 in the kinase activation loop of Inhibitor of κB kinase beta (IKKβ) occur in multiple myeloma, spleen marginal zone lymphoma and mantle cell lymphoma. Previously, we demonstrated that these result in constitutive kinase activation and stimulate Signal Transducer and Activator of Transcription 3 (STAT3). This work also identified K147 as a site of K63-linked regulatory ubiquitination required for activation of signaling pathways. We now present a more detailed analysis of ubiquitination sites together with a comprehensive examination of the signaling pathways activated by IKKβ K171E mutants...
2018: PloS One
Haiwen Li, Yu Cui, Jun Wei, Chao Liu, Yuhan Chen, Chun-Ping Cui, Lei Li, Xueli Zhang, Lingqiang Zhang
The bone morphogenetic protein (BMP)-Smad signaling pathway plays a crucial role in the control of bone homeostasis by regulating osteoblast activity. It is known that the ubiquitin ligase Smad ubiquitination regulatory factor (Smurf)1 is a master negative regulator of BMP signaling, but how its stability and activity are regulated remains poorly understood. Our study showed that valosin-containing protein/p97, the mutations of which lead to rare forms of Paget's disease of bone (PDB)-like syndrome-such as inclusion body myopathy (IBM) associated with Paget's disease of bone and frontotemporal dementia (IBM-PFD)-together with its adaptor nuclear protein localization (NPL)4, specifically interact with Smurf1 and deliver the ubiquitinated Smurf1 for degradation...
October 18, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
Yuji Masuda, Satoshi Mitsuyuki, Rie Kanao, Asami Hishiki, Hiroshi Hashimoto, Chikahide Masutani
DNA-damage tolerance protects cells via at least two sub-pathways regulated by proliferating cell nuclear antigen (PCNA) ubiquitination in eukaryotes: translesion DNA synthesis (TLS) and template switching (TS), which are stimulated by mono- and polyubiquitination, respectively. However, how cells choose between the two pathways remains unclear. The regulation of ubiquitin ligases catalyzing polyubiquitination, such as helicase-like transcription factor (HLTF), could play a role in the choice of pathway. Here, we demonstrate that the ligase activity of HLTF is stimulated by double-stranded DNA via HIRAN domain-dependent recruitment to stalled primer ends...
October 18, 2018: Nucleic Acids Research
Xiao-Fei Ding, Jie Chen, Jun Zhou, Guang Chen, Ying-Liang Wu
Previous research has revealed that the von-Hippel-Lindau tumor suppressor protein (pVHL) may downregulate never-in-mitosis A-related kinase 8 (NEK8) via hypoxia-inducible factor-α (HIF-α). The HIF-independent functions of pVHL also serve an important role in its tumor-suppressor action. In the present study, the association between pVHL and NEK8 was demonstrated in the human gastric cancer cell line, SGC-7901, indicating a direct interaction of pVHL with NEK8. Subsequently, it was reported that MG-132, a specific proteasome inhibitor, may attenuate pVHL overexpression-induced reductions in NEK8 protein expression levels...
November 2018: Oncology Letters
Jian-Fang Bai, Yu-Kun Wang, Peng Wang, Shao-Hua Yuan, Jian-Gang Gao, Wen-Jing Duan, Na Wang, Feng-Ting Zhang, Wen-Jie Zhang, Meng-Ying Qin, Chang-Ping Zhao, Li-Ping Zhang
BACKGROUND: COI (CORONATINE INSENSITIVE), an F-box component of the Skp1-Cullin-F-box protein (SCFCOI1 ) ubiquitin E3 ligase, plays important roles in the regulation of plant growth and development. Recent studies have shown that COIs are involved in pollen fertility. In this study, we identified and characterized COI genes in the wheat genome and analyzed expression patterns under abiotic stress. RESULTS: A total of 18 COI candidate sequences for 8 members of COI gene family were isolated in wheat (Triticum aestivum L...
October 17, 2018: BMC Genomics
Jian Yang, Meng-Yang Xie, Lan Wang, Zhi-Li Yang, Zhi-Hui Tian, Zhi-Ye Wang, Ji-Ming Xu, Bao-Hui Liu, Liang-Wei Deng, Chuan-Zao Mao, Hong-Hui Lin
Phosphate (Pi), as the main form of phosphorus that can be absorbed by plants, is one of the most limiting macro-nutrients for plants. However, the mechanism for maintaining Pi homeostasis in rice (Oryza sativa) is still not well understood. We identified a Pi-starvation-induced E3 ligase (OsPIE1) in rice. Using an in vitro self-ubiquitination assay, we determined the E3 ligase activities of OsPIE1. Using GUS staining and GFP detection, we analyzed tissue expression patterns of OsPIE1 and the subcellular localization of its encoded protein...
October 17, 2018: Plant & Cell Physiology
Xiaoguang Liu, Michaeline Hebron, Wangke Shi, Irina Lonskaya, Charbel E-H Moussa
Ubiquitin specific proteases (USPs) are de-ubiquitinases that control protein ubiquitination cycle. The role of de-ubiquitinases is poorly understood in neurodegenerative diseases. We found that USP13 is overexpressed in post-mortem Parkinson's disease (PD) brain. We investigated whether changes in USP13 levels can affect two molecules, parkin and alpha-synuclein, that are implicated in PD pathogenesis. Parkin is an E3 ubiquitin ligase that is regulated by ubiquitination and targets certain proteins for degradation, and alpha-synuclein may be ubiquitinated and recycled in the normal brain...
October 16, 2018: Human Molecular Genetics
Madina Mahesutihan, Weinan Zheng, Liang Cui, Yun Li, Pengtao Jiao, Wenxian Yang, Wei Liu, Jing Li, Wenhui Fan, Limin Yang, Wenjun Liu, Lei Sun
Cyclophilin A (CypA) is a peptidyl-prolyl cis/trans isomerase that interacts with the matrix protein (M1) of influenza A virus (IAV) and restricts virus replication by regulating the ubiquitin-proteasome-mediated degradation of M1. However, the mechanism by which CypA regulates M1 ubiquitination remains unknown. In this study, we reported that E3 ubiquitin ligase AIP4 promoted K48-linked ubiquitination of M1 at K102 and K104, and accelerated ubiquitin-proteasome-mediated degradation of M1. The recombinant IAV with mutant M1 (K102R/K104R) could not be rescued, suggesting that the ubiquitination of M1 at K102/K104 was essential for IAV replication...
October 16, 2018: Virologica Sinica
Huijiao Liu, Jiangnan Wang, Yun Liu, Lelin Hu, Chunfeng Zhang, Baocai Xing, Xiaojuan Du
The nucleolar protein hUTP14a promotes p53 degradation and possesses an oncogene potential. Here, we report that hUTP14a promotes degradation of tumor suppressor retinoblastoma (RB) protein. Sequences alignment showed that hUTP14a contains the RB-binding PENF motif in its C-terminus. We showed that hUTP14a interacted with RB in vivo and in vitro. Further, hUTP14a promoted polyubiquitination and proteasome-dependent turnover of RB. Importantly, purified Flag-hUTP14a facilitated RB ubiquitination in vitro, demonstrating that hUTP14a is an ubiquitin E3 ligase for RB...
November 2018: Biochimica et biophysica acta. Molecular cell research
Ziming Huang, Yong Cai, Chenchen Yang, Zhen Chen, Hong Sun, Yingying Xu, Wei Chen, Dafu Xu, Wenze Tian, Haixiao Wang
Background and objective: RNF6, an E3 ligase, has been reported to play an important role in the tumorigenesis in several tissues, but its role in gastric cancer is still unknown. In this study, we aimed to investigate the biological function and molecular mechanisms of RNF6 in gastric cancer. Materials and methods: The expression levels of RNF6 were detected by quantitative real-time PCR (qRT-PCR) and immunoblotting in gastric cancer tissues and cell lines. Cell Counting Kit-8 assay was performed to evaluate cell proliferation...
2018: OncoTargets and Therapy
Jae Min Lee, Sun Sil Choi, Yo Han Lee, Keon Woo Khim, Sora Yoon, Byung-Gyu Kim, Dougu Nam, Pann-Ghill Suh, Kyungjae Myung, Jang Hyun Choi
Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent transcription factor that regulates adipocyte differentiation and glucose homeostasis. The transcriptional activity of PPARγ is regulated not only by ligands but also by post-translational modifications (PTMs). In this study, we demonstrate that a novel E3 ligase of PPARγ, tripartite motif-containing 25 (TRIM25), directly induced the ubiquitination of PPARγ, leading to its proteasome-dependent degradation. During adipocyte differentiation, both TRIM25 mRNA and protein expression significantly decreased and negatively correlated with the expression of PPARγ...
October 15, 2018: Experimental & Molecular Medicine
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