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Youbao Sha, Lang Rao, Carmine Settembre, Andrea Ballabio, N Tony Eissa
TFEB is a master regulator for transcription of genes involved in autophagy and lysosome biogenesis. Activity of TFEB is inhibited upon its serine phosphorylation by mTOR The overall mechanisms by which TFEB activity in the cell is regulated are not well elucidated. Specifically, the mechanisms of TFEB turnover and how they might influence its activity remain unknown. Here, we show that STUB1, a chaperone-dependent E3 ubiquitin ligase, modulates TFEB activity by preferentially targeting inactive phosphorylated TFEB for degradation by the ubiquitin-proteasome pathway...
September 1, 2017: EMBO Journal
Jin Cheng, Feng Ye, Guorong Dan, Yuanpeng Zhao, Jiqing Zhao, Zhongmin Zou
N-methyl-2,2-di(chloroethyl)amine (HN2) is a kind of bifunctional alkyltating agent, which can react with nucleophilic groups in DNA and/or protein to form HN2-bridged crosslinking of target molecules, such as DNA-protein crosslinkings (DPC). O6 -methylguanine-DNA methyltransferase (MGMT) is a DNA damage repair enzyme which solely repairs alkyl adduct on DNA directly. However, MGMT was detected to act as a protein cross-linked with DNA via alkylation in presence of HN2, and unexpectedly turned into a DNA damage enhancer in the form of MGMT-DNA cross-link (mDPC)...
August 15, 2017: Toxicology
William Ka Fai Tse
Deconjugation of ubiquitin and/or ubiqutin-like modified substrates is essential to maintain a sufficient free ubiquitin within the cell. Deubiquitinases (DUBs) play a key role in the process. Besides, DUBs also play several important regulatory roles in cellular processes. However, our knowledge of their developmental roles are limited. The report here aims to study their potential roles in craniofacial development. Based on the previous genome-wide study in 2009, we selected 36 DUBs to perform the morpholino (MO) knockdown in this study, followed by the Alcian blue cartilage staining at 5 days post-fertilization (dpf) larvae to investigate the facial development...
June 10, 2017: Biochemical and Biophysical Research Communications
Yi Zheng, Jie Li, Chenwei Pan, Guangyao Zhou, Lu Zhuge, Lingxiang Jin, Peipei Fang
Recently, more and more evidences unveiled that ubiquitin-proteasome system (UPS) makes an important contribution to the occurrence and development of cancer. HERC4 is one identified Ubiqutin ligase E3, a member of UPS. Although some studies showed that HERC4 abnormally expresses in many cancer cells, till now, nothing has been reported about the function of HERC4 in the development of hepatoma carcinoma. To this end, in this study, we studied the function of HERC4 for the first time in hepatoma carcinoma cells...
June 2017: DNA and Cell Biology
Mingyue Gou, Quansheng Huang, Weiqiang Qian, Zemin Zhang, Zhenhua Jia, Jian Hua
The small ubiqutin-like modifier E3 ligase SIZ1 regulates multiple processes in Arabidopsis, including salicylic-acid-dependent immune responses. However, the targets of SIZ1 in plant immunity are not known. Here, we provide evidence that the plant immune receptor nucleotide-binding leucine-rich repeat gene SNC1 partially mediates the regulation of plant immunity by SIZ1. The siz1 loss-of-function mutant has an autoimmune phenotype that is dependent on SNC1 and temperature. Overexpression of SIZ1 partially rescues autoimmune mutant phenotypes induced by activation or overaccumulation of SNC1, and the SNC1 protein amount is attenuated by SIZ1 overexpression...
April 2017: Molecular Plant-microbe Interactions: MPMI
Chao Zhang, Gideon Bollag
<b/> Blocking dimerization and stimulating protein degradation are two mechanisms known to inhibit BRAF activity. The study reported by Wan and colleagues identifies BRAF as a substrate of the APC/CFZR1 -ubiqutin-proteasome system. The interaction between FZR1 and BRAF also induces a conformational change that disrupts BRAF dimerization. These findings identify a dynamic interplay between FZR1 and BRAF with strong implications for cell-fate determination and the tumor suppressor role of FZR1. Cancer Discov; 7(4); 356-8...
April 2017: Cancer Discovery
Evangelos Koustas, Michalis V Karamouzis, Chrysovalantou Mihailidou, Dimitrios Schizas, Athanasios G Papavassiliou
The epidermal growth factor receptor (EGFR) and its associated pathway is a critical key regulator of CRC development and progression. The monoclonal antibodies (MoAbs) cetuximab and panitumumab, directed against EGFR, represent a major step forward in the treatment of metastatic colorectal cancer (mCRC), in terms of progression-free survival and overall survival in several clinical trials. However, the activity of anti-EGFR MoAbs appears to be limited to a subset of patients with mCRC. Studies have highlighted that acquired-resistance to anti-EGFR MoAbs biochemically converge into Ras/Raf/Mek/Erk and PI3K/Akt/mTOR pathways...
June 28, 2017: Cancer Letters
Juan J Gu, Gregory P Kaufman, Cory Mavis, Myron S Czuczman, Francisco J Hernandez-Ilizaliturri
The ubiqutin-proteasome system (UPS) plays a role in rituximab-chemotherapy resistance and bortezomib (BTZ) possesses caspase-dependent (i.e. Bak stabilization) and a less characterized caspase-independent mechanism-of-action(s). Here, we define BTZ-induced caspase-independent cell death pathways. A panel of rituximab-sensitive (RSCL), rituximab-resistant cell lines (RRCL) and primary tumor cells derived from lymphoma patients (N = 13) were exposed to BTZ. Changes in cell viability, cell-cycle, senescence, and mitotic index were quantified...
February 21, 2017: Oncotarget
Subhadip Mukhopadhyay, Prajna Paramita Naik, Prashanta Kumar Panda, Niharika Sinha, Durgesh Nandini Das, Sujit Kumar Bhutia
Mitophagy is a highly specialised type of autophagy that plays an important role in regulating mitochondrial dynamics and controls cellular quality during stress. In this study, we established that serum starvation led to induction of cellular inhibitor of apoptosis protein-1 (cIAP1), which regulates mitophagy through ubiquitination. Importantly, gain and loss of function of cIAP1 resulted in concomitant alteration in mitophagy confirming the direct implication of cIAP1 in induction of mitophagy. Interestingly, it was observed that cIAP1 translocated to mitochondria to associate with TOM20, Ulk1, and LC3 to initiate mitophagy...
October 28, 2016: Biochemical and Biophysical Research Communications
Frederick C Nucifora, Leslie G Nucifora, Chee-Hoe Ng, Nicolas Arbez, Yajuan Guo, Elaine Roby, Vered Shani, Simone Engelender, Dong Wei, Xiao-Fang Wang, Tianxia Li, Darren J Moore, Olga Pletnikova, Juan C Troncoso, Akira Sawa, Ted M Dawson, Wanli Smith, Kah-Leong Lim, Christopher A Ross
A common genetic form of Parkinson's disease (PD) is caused by mutations in LRRK2. We identify WSB1 as a LRRK2 interacting protein. WSB1 ubiquitinates LRRK2 through K27 and K29 linkage chains, leading to LRRK2 aggregation and neuronal protection in primary neurons and a Drosophila model of G2019S LRRK2. Knocking down endogenous WSB1 exacerbates mutant LRRK2 neuronal toxicity in neurons and the Drosophila model, indicating a role for endogenous WSB1 in modulating LRRK2 cell toxicity. WSB1 is in Lewy bodies in human PD post-mortem tissue...
June 7, 2016: Nature Communications
Xin Liu, Hongyuan Li, Lingxia Liu, Yang Lu, Yanyan Gao, Pengyu Geng, Xiaoxue Li, Baiqu Huang, Yu Zhang, Jun Lu
The cap 'n' collar (CNC) family of transcription factors play important roles in resistance of oxidative and electrophilic stresses. Among the CNC family members, NF-E2-related factor 2 (Nrf2) is critical for regulating the antioxidant and phase II enzymes through antioxidant response element (ARE)-mediated transactivation. The activity of Nrf2 is controlled by a variety of post-translational modifications, including phosphorylation, ubiquitination, acetylation and sumoylation. Here we demonstrate that the arginine methyltransferase-1 (PRMT1) methylates Nrf2 protein at a single residue of arginine 437, both in vitro and in vivo...
August 2016: Biochimica et Biophysica Acta
Dragana A M Catici, Hope E Amos, Yi Yang, Jean M H van den Elsen, Christopher R Pudney
To understand complex molecular interactions, it is necessary to account for molecular flexibility and the available equilibrium of conformational states. Only a small number of experimental approaches can access such information. Potentially steady-state red edge excitation shift (REES) spectroscopy can act as a qualitative metric of changes to the protein free energy landscape (FEL) and the equilibrium of conformational states. First, we validate this hypothesis using a single Trp-containing protein, NF-κB essential modulator (NEMO)...
June 2016: FEBS Journal
Xingqiao Xie, Faxiang Li, Yuanyuan Wang, Yingli Wang, Zhijie Lin, Xiaofang Cheng, Jianping Liu, Changbin Chen, Lifeng Pan
The autophagy receptor CALCOCO2/NDP52 functions as a bridging adaptor and plays an essential role in the selective autophagic degradation of invading pathogens by specifically recognizing ubiquitin-coated intracellular pathogens and subsequently targeting them to the autophagic machinery; thereby it is required for innate immune defense against a range of infectious pathogens in mammals. However, the mechanistic basis underlying CALCOCO2-mediated specific recognition of ubiqutinated pathogens is still unknown...
2015: Autophagy
Lu-jing Ren, Xiao-yan Zhuang, Sheng-lan Chen, Xiao-jun Ji, He Huang
ω-3 fatty acids play significant roles in brain development and cardiovascular disease prevention and have been widely used in food additives and the pharmaceutical industry. The aim of this study was to assess the feasibility of ω-3 desaturase for regulating fatty acid composition and sterol content in Schizochytrium sp. The exogenous ω-3 desaturase gene driven by ubiqutin promoter was introduced by 18S homologous sequence to the genome of Schizochytrium sp. Genetically modified strains had greater size and lower polar lipids than wild type strains...
November 11, 2015: Journal of Agricultural and Food Chemistry
Yoshinori Katsuragi, Yoshinobu Ichimura, Masaaki Komatsu
p62/SQSTM1 is a stress-inducible cellular protein that is conserved among metazoans but not in plants and fungi. p62/SQSTM1 has multiple domains that mediate its interactions with various binding partners and it serves as a signaling hub for diverse cellular events such as amino acid sensing and the oxidative stress response. In addition, p62/SQSTM1 functions as a selective autophagy receptor for degradation of ubiqutinated substrates. In the present review, we describe the current knowledge about p62 with regard to mammalian target of rapamycin complex 1 activation, the Keap1-Nrf2 pathway and selective autophagy...
December 2015: FEBS Journal
Christian M Girgis, Kuan Minn Cha, Peter J Houweling, Renuka Rao, Nancy Mokbel, Mike Lin, Roderick J Clifton-Bligh, Jenny E Gunton
Vitamin D deficiency is associated with muscle weakness, pain, and atrophy. Serum vitamin D predicts muscle strength and age-related muscle changes. However, precise mechanisms by which vitamin D affects skeletal muscle are unclear. To address this question, this study characterizes the muscle phenotype and gene expression of mice with deletion of vitamin D receptor (VDRKO) or diet-induced vitamin D deficiency. VDRKO and vitamin D-deficient mice had significantly weaker grip strength than their controls. Weakness progressed with age and duration of vitamin D deficiency, respectively...
December 2015: Calcified Tissue International
Mi Kyung Park, Chang Hoon Lee
Toxicants can perturb cellular homeostasis by modifying phosphorylation-based signaling. In the present study, we examined the effects of cerulein, an inducer of acute pancreatitis, on keratin 8 (K8) phosphorylation. We found that cerulein dose-dependently induced K8 phosphorylation and perinuclear reorganization in PANC-1 cells, thus leading to migration and invasion. The extracellular signal-regulated kinases (ERK) inhibitor U0126 suppressed cerulein-induced phosphorylation of serine 431 and reorganization of K8...
December 2016: Environmental Toxicology
Karolina Matković, Małgorzata Mitkiewicz, Janusz Matuszyk
Type I interferons (IFNs) are important in the immune response. After pathogen detection, host cells rapidly trigger innate immune mechanisms such as inflammatory cytokines production, thus leading to the eradication of the invading virus. Such mechanisms engage signaling cascades which, in the initial phase of infection, lead to the activation of the NF-κB pathway and IFN regulatory factors (IRF-3, IRF-7) which directly control the production of IFNs. Proper regulation of IFN induction takes place by ubiqutination and allows to maintain a balance between the activation and inhibition of the immune system response due to an infection...
July 27, 2015: Postȩpy Higieny i Medycyny Doświadczalnej
H Ogi, Y Sakuraba, R Kitagawa, L Xiao, C Shen, M A Cynthia, S Ohta, M A Arnold, N Ramirez, P J Houghton, K Kitagawa
Sgt1/Sugt1, a cochaperone of Hsp90, is involved in several cellular activities including Cullin E3 ubiqutin ligase activity. The high level of Sgt1 expression in colorectal and gastric tumors suggests that Sgt1 is involved in tumorigenesis. Here, we report that Sgt1 is overexpressed in colon, breast and lung tumor tissues and in Ewing sarcoma and rhabdomyosarcoma xenografts. We also found that Sgt1 heterozygous knockout resulted in suppressed Hras-mediated transformation in vitro and tumor formation in p53(-/-) mouse embryonic fibroblast cells and significantly increased survival of p53(-/-) mice...
2015: Oncogenesis
Andrea Du Toit
No abstract text is available yet for this article.
April 23, 2015: Nature Reviews. Molecular Cell Biology
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