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https://www.readbyqxmd.com/read/27932573/fine-tuning-of-ulk1-mrna-and-protein-levels-is-required-for-autophagy-oscillation
#1
Francesca Nazio, Marianna Carinci, Cristina Valacca, Pamela Bielli, Flavie Strappazzon, Manuela Antonioli, Fabiola Ciccosanti, Carlo Rodolfo, Silvia Campello, Gian Maria Fimia, Claudio Sette, Paolo Bonaldo, Francesco Cecconi
Autophagy is an intracellular degradation pathway whose levels are tightly controlled to secure cell homeostasis. Unc-51-like kinase 1 (ULK1) is a conserved serine-threonine kinase that plays a central role in the initiation of autophagy. Here, we report that upon autophagy progression, ULK1 protein levels are specifically down-regulated by the E3 ligase NEDD4L, which ubiquitylates ULK1 for degradation by the proteasome. However, whereas ULK1 protein is degraded, ULK1 mRNA is actively transcribed. Upon reactivation of mTOR-dependent protein synthesis, basal levels of ULK1 are promptly restored, but the activity of newly synthesized ULK1 is inhibited by mTOR...
December 8, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27932492/novel-regulatory-roles-of-mff-and-drp1-in-e3-ubiquitin-ligase-march5-dependent-degradation-of-mid49-and-mcl1-and-control-of-mitochondrial-dynamics
#2
Edward Cherok, Shan Xu, Sunan Li, Shweta Das, W Alex Meltzer, Michal Zalzman, Chunxin Wang, Mariusz Karbowski
MARCH5, an OMM-associated E3 ubiquitin ligase, controls mitochondrial function. Despite its importance, the mechanism and factors controlling MARCH5 activity are largely unknown. Here we report that the MARCH5 C-terminal domain plays a critical role in degradation of MARCH5 substrates, likely by facilitating release of ubiquitinated proteins from the OMM. We also found that the mitochondrial fission proteins Drp1 and Mff negatively regulate MARCH5's activity toward MiD49 and Mcl1. Knockouts of either Drp1 or Mff led to reduced expression, shorter half-lives, and increased ubiquitination of MiD49 and Mcl1...
December 8, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27932386/aberrant-expression-of-fbxo2-disrupts-glucose-homeostasis-through-ubiquitin-mediated-degradation-of-insulin-receptor-in-obese-mice
#3
Bin Liu, Han Lu, Duanzhuo Li, Xuelian Xiong, Lu Gao, Zhixiang Wu, Yan Lu
Insulin resistance is a critical factor in the development of metabolic disorders, including type 2 diabetes (T2DM). However, its molecular mechanisms remain incompletely understood. In the present study, we found that F-box only protein 2 (FBXO2), a substrate recognition component of SKP1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase complex, were up-regulated in livers of obese mice. Furthermore, using a protein purification approach combined with high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS), we carried out a system-wide screening of FBXO2 substrates, in which insulin receptor (IR) was identified as a substrate for FBXO2...
December 8, 2016: Diabetes
https://www.readbyqxmd.com/read/27929533/the-yersinia-type-iii-secretion-effector-yopm-is-an-e3-ubiquitin-ligase-that-induced-necrotic-cell-death-by-targeting-nlrp3
#4
Congwen Wei, Ying Wang, Zongmin Du, Kai Guan, Ye Cao, Huiying Yang, Pengyu Zhou, Feixiang Wu, Jiankang Chen, Penghao Wang, Zirui Zheng, Pingping Zhang, Yanhong Zhang, Shengli Ma, Ruifu Yang, Hui Zhong, Xiang He
Yersinia pestis uses type III effector proteins to target eukaryotic signaling systems. The Yersinia outer protein (Yop) M effector from the Y. pestis strain is a critical virulence determinant; however, its role in Y. pestis pathogenesis is just beginning to emerge. Here we first identify YopM as the structural mimic of the bacterial IpaH E3 ligase family in vitro, and establish that the conserved CLD motif in its N-terminal is responsible for the E3 ligase function. Furthermore, we show that NLRP3 is a novel target of the YopM protein...
December 8, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27929086/the-e3-ubiquitin-ligase-trim31-attenuates-nlrp3-inflammasome-activation-by-promoting-proteasomal-degradation-of-nlrp3
#5
Hui Song, Bingyu Liu, Wanwan Huai, Zhongxia Yu, Wenwen Wang, Jing Zhao, Lihui Han, Guosheng Jiang, Lining Zhang, Chengjiang Gao, Wei Zhao
The NLRP3 inflammasome has a fundamental role in host defence against microbial pathogens and its deregulation may cause diverse inflammatory diseases. NLRP3 protein expression is a rate-limiting step for inflammasome activation, thus its expression must be tightly controlled to maintain immune homeostasis and avoid detrimental effects. However, how NLRP3 expression is regulated remains largely unknown. In this study, we identify E3 ubiquitin ligase TRIM31 as a feedback suppressor of NLRP3 inflammasome. TRIM31 directly binds to NLRP3, promotes K48-linked polyubiquitination and proteasomal degradation of NLRP3...
December 8, 2016: Nature Communications
https://www.readbyqxmd.com/read/27927750/mdm2-as-a-chromatin-modifier
#6
REVIEW
Magdalena Wienken, Ute M Moll, Matthias Dobbelstein
Mdm2 is the key negative regulator of the tumour suppressor p53, making it an attractive target for anti-cancer drug design. We recently identified a new role of Mdm2 in gene repression through its direct interaction with several proteins of the polycomb group (PcG) family. PcG proteins form polycomb repressive complexes PRC1 and PRC2. PRC2 (via EZH2) mediates histone 3 lysine 27 (H3K27) trimethylation, and PRC1 (via RING1B) mediates histone 2A lysine 119 (H2AK119) monoubiquitination. Both PRCs mostly support a compact and transcriptionally silent chromatin structure...
November 9, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27927749/modulation-of-the-p53-mdm2-interplay-by-hausp-inhibitors
#7
REVIEW
Omid Tavana, Wei Gu
It is well established that both p53 and MDM2 are short-lived proteins whose stabilities are tightly controlled through ubiquitination-mediated degradation. Although numerous studies indicate that the MDM2 E3 ligase activity, as well as the protein-protein interaction between p53 and MDM2, is the major focus for this regulation, emerging evidence suggests that the deubiquitinase herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7) plays a critical role. Furthermore, HAUSP inhibition elevates p53 stability and might be beneficial for therapeutic purposes...
December 6, 2016: Journal of Molecular Cell Biology
https://www.readbyqxmd.com/read/27927016/inhibition-of-cathepsin-s-induces-mitochondrial-ros-that-sensitizes-trail-mediated-apoptosis-through-p53-mediated-down-regulation-of-bcl-2-and-c-flip
#8
Bo Ram Seo, Kyoung-Jin Min, Seon Min Woo, Misun Choe, Kyeong Sook Choi, Young-Kyung Lee, Gyesoon Yoon, Taeg Kyu Kwon
AIMS: Cathepsin S is highly expressed in various cancer cells, and it has pro-tumoral effects, including promotion of migration, invasion and neovascularization. In this study, we show that inhibition of cathepsin S could sensitize cancer cells to TRAIL-mediated apoptosis. RESULTS: An inhibitor of cathepsin S (Z-FL-COCHO; ZFL) markedly induced apoptosis in human renal cancer cells treated with TRAIL. In contrast, combined treatment with ZFL and TRAIL had no effect on normal cells...
December 7, 2016: Antioxidants & Redox Signaling
https://www.readbyqxmd.com/read/27926943/the-mouse-cytomegalovirus-gene-m42-targets-surface-expression-of-the-protein-tyrosine-phosphatase-cd45-in-infected-macrophages
#9
Nadine Thiel, Kirsten A Keyser, Niels A W Lemmermann, Jennifer D Oduro, Karen Wagner, Carina Elsner, Anne Halenius, Tihana Lenac Roviš, Melanie M Brinkmann, Stipan Jonjić, Luka Cicin-Sain, Martin Messerle
The receptor-like protein tyrosine phosphatase CD45 is expressed on the surface of cells of hematopoietic origin and has a pivotal role for the function of these cells in the immune response. Here we report that following infection of macrophages with mouse cytomegalovirus (MCMV) the cell surface expression of CD45 is drastically diminished. Screening of a set of MCMV deletion mutants allowed us to identify the viral gene m42 of being responsible for CD45 down-modulation. Moreover, expression of m42 independent of viral infection upon retroviral transduction of the RAW264...
December 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27925369/conventional-and-unconventional-ubiquitination-in-plant-immunity
#10
REVIEW
Bangjun Zhou, Lirong Zeng
Ubiquitination is one of the most abundant types of protein post-translational modifications (PTMs) in plant cells. The importance of ubiquitination in the regulation of many aspects of plant immunity has been increasingly appreciated in recent years. Most of the studies linking ubiquitination to the plant immune system, however, have been focused on the E3 ubiquitin ligases and the conventional ubiquitination that leads to degradation of the substrate proteins by the 26S proteasome. By contrast, our knowledge about the role of unconventional ubiquitination that often plays non-degradative, regulatory role remains a significant gap...
December 7, 2016: Molecular Plant Pathology
https://www.readbyqxmd.com/read/27924031/ubiquitylation-dependent-regulation-of-neil1-by-mule-and-trim26-is-required-for-the-cellular-dna-damage-response
#11
Matthew J Edmonds, Rachel J Carter, Catherine M Nickson, Sarah C Williams, Jason L Parsons
Endonuclease VIII-like protein 1 (NEIL1) is a DNA glycosylase involved in initiating the base excision repair pathway, the major cellular mechanism for repairing DNA base damage. Here, we have purified the major E3 ubiquitin ligases from human cells responsible for regulation of NEIL1 by ubiquitylation. Interestingly, we have identified two enzymes that catalyse NEIL1 polyubiquitylation, Mcl-1 ubiquitin ligase E3 (Mule) and tripartite motif 26 (TRIM26). We demonstrate that these enzymes are capable of polyubiquitylating NEIL1 in vitro, and that both catalyse ubiquitylation of NEIL1 within the same C-terminal lysine residues...
October 18, 2016: Nucleic Acids Research
https://www.readbyqxmd.com/read/27923907/deubiquitinase-usp13-maintains-glioblastoma-stem-cells-by-antagonizing-fbxl14-mediated-myc-ubiquitination
#12
Xiaoguang Fang, Wenchao Zhou, Qiulian Wu, Zhi Huang, Yu Shi, Kailin Yang, Cong Chen, Qi Xie, Stephen C Mack, Xiuxing Wang, Angel M Carcaboso, Andrew E Sloan, Gaoliang Ouyang, Roger E McLendon, Xiu-Wu Bian, Jeremy N Rich, Shideng Bao
Glioblastoma is the most lethal brain tumor and harbors glioma stem cells (GSCs) with potent tumorigenic capacity. The function of GSCs in tumor propagation is maintained by several core transcriptional regulators including c-Myc. c-Myc protein is tightly regulated by posttranslational modification. However, the posttranslational regulatory mechanisms for c-Myc in GSCs have not been defined. In this study, we demonstrate that the deubiquitinase USP13 stabilizes c-Myc by antagonizing FBXL14-mediated ubiquitination to maintain GSC self-renewal and tumorigenic potential...
December 6, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27922847/apolipoprotein-e-metabolism-and-functions-in-brain-and-its-role-in-alzheimer-s-disease
#13
Fan Liao, Hyejin Yoon, Jungsu Kim
PURPOSE OF REVIEW: APOE4 genotype is the strongest genetic risk factor for Alzheimer's disease. Prevailing evidence suggests that amyloid β plays a critical role in Alzheimer's disease. The objective of this article is to review the recent findings about the metabolism of apolipoprotein E (ApoE) and amyloid β and other possible mechanisms by which ApoE contributes to the pathogenesis of Alzheimer's disease. RECENT FINDINGS: ApoE isoforms have differential effects on amyloid β metabolism...
December 5, 2016: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/27922670/downregulation-of-laptm5-suppresses-cell-proliferation-and-viability-inducing-cell-cycle-arrest-at-g0-g1-phase-of-bladder-cancer-cells
#14
Liang Chen, Gang Wang, Yi Luo, Yongzhi Wang, Conghua Xie, Wei Jiang, Yu Xiao, Guofeng Qian, Xinghuan Wang
Our transcriptome analysis revealed in bladder cancer (BCa) tissues a significant induction of lysosomal-associated multispanning membrane protein 5 (LAPTM5), a lysosomal membrane protein preferentially expressing in immune cells and hematopoietic cells. Transportation of LAPTM5 from Golgi to lysosome could be inhibited by deficiency of Nedd4, a key member of E3 ubiquitin ligase family overexpressing in invasive BCa and promoting its progression. Therefore, we hypothesize that LAPTM5 may be closely correlated with BCa tumorigenesis...
December 5, 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/27922665/translocation-of-bbap-from-the-cytoplasm-to-the-nucleus-reduces-the-metastatic-ability-of-vemurafenib-resistant-skmel28-cells
#15
Nguyen Dinh Thang, Nguyen Van Minh, Pham Thu Huong
To the best of our knowledge, the present study is the first to demonstrate that treatment of vemurafenib-resistant SKMEL28 (SKMEL28-R) cells with paclitaxel leads to a shift in localization of the E3-ligase BBAP from the cytoplasm to the nucleus, consequently decreasing the metastatic ability of this cell line. The present study revealed that the movement of BBAP from the cytoplasm to nucleus initiated a change in cell morphology. In addition, the translocation of BBAP led to a decrease of metastatic characteristics in SKMEL28‑R cells, including migration and invasion via downregulation of the phosphorylated form of focal adhesion kinase and N‑cadherin, as well as an upregulation of p21 and E-cadherin...
December 2, 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27920276/studies-of-recombinant-twa1-reveal-constitutive-dimerisation
#16
Ore Francis, Genevieve E Baker, Paul R Race, Josephine C Adams
The mammalian muskelin/RanBP9/CTLH complex and the S. cerevisiae GID complex are large, multi-protein complexes that each contain a RING E3 ubiquitin ligase. The yeast GID complex acts to degrade a key enzyme of gluconeogenesis, fructose 1,6-bisphosphatase, under conditions of abundant fermentable carbon sources. However, the assembly and functions of the mammalian complex remain poorly understood. A striking feature of these complexes is the presence of multiple proteins that contain contiguous lissencephaly-1 homology (LisH), C-terminal to LisH (CTLH) and C-terminal CT11-RanBP9 (CRA) domains...
December 5, 2016: Bioscience Reports
https://www.readbyqxmd.com/read/27919079/receptor-usage-dictates-hiv-1-restriction-by-human-trim5%C3%AE-in-dendritic-cell-subsets
#17
Carla M S Ribeiro, Ramin Sarrami-Forooshani, Laurentia C Setiawan, Esther M Zijlstra-Willems, John L van Hamme, Wikky Tigchelaar, Nicole N van der Wel, Neeltje A Kootstra, Sonja I Gringhuis, Teunis B H Geijtenbeek
The most prevalent route of HIV-1 infection is across mucosal tissues after sexual contact. Langerhans cells (LCs) belong to the subset of dendritic cells (DCs) that line the mucosal epithelia of vagina and foreskin and have the ability to sense and induce immunity to invading pathogens. Anatomical and functional characteristics make LCs one of the primary targets of HIV-1 infection. Notably, LCs form a protective barrier against HIV-1 infection and transmission. LCs restrict HIV-1 infection through the capture of HIV-1 by the C-type lectin receptor Langerin and subsequent internalization into Birbeck granules...
December 7, 2016: Nature
https://www.readbyqxmd.com/read/27918549/a-hypoxia-responsive-traf6-atm-h2ax-signalling-axis-promotes-hif1%C3%AE-activation-tumorigenesis-and%C3%A2-metastasis
#18
Abdol-Hossein Rezaeian, Chien-Feng Li, Ching-Yuan Wu, Xian Zhang, Jorge Delacerda, M James You, Fei Han, Zhen Cai, Yun Seong Jeong, Guoxiang Jin, Liem Phan, Ping-Chieh Chou, Mong-Hong Lee, Mien-Chie Hung, Dos Sarbassov, Hui-Kuan Lin
The understanding of how hypoxia stabilizes and activates HIF1α in the nucleus with related oncogenic signals could revolutionize targeted therapy for cancers. Here, we find that histone H2AX displays oncogenic activity by serving as a crucial regulator of HIF1α signalling. H2AX interacts with HIF1α to prevent its degradation and nuclear export in order to allow successful VHL-independent HIF1α transcriptional activation. We show that mono-ubiquitylation and phosphorylation of H2AX, which are strictly mediated by hypoxia-induced E3 ligase activity of TRAF6 and ATM, critically regulate HIF1α-driven tumorigenesis...
December 5, 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/27917940/ubiquitin-ligase-nedd4-regulates-ppar%C3%AE-stability-and-adipocyte-differentiation-in-3t3-l1-cells
#19
Jing Jing Li, Ruishan Wang, Rati Lama, Xinjiang Wang, Z Elizabeth Floyd, Edwards A Park, Francesca-Fang Liao
Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated nuclear receptor which controls lipid and glucose metabolism. It is also the master regulator of adipogenesis. In adipocytes, ligand-dependent PPARγ activation is associated with proteasomal degradation; therefore, regulation of PPARγ degradation may modulate its transcriptional activity. Here, we show that neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4), an E3 ubiquitin ligase, interacts with the hinge and ligand binding domains of PPARγ and is a bona fide E3 ligase for PPARγ...
December 5, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27917682/the-preclinical-discovery-and-development-of-bortezomib-for-the-treatment-of-mantle-cell-lymphoma
#20
Richard Arkwright, Tri Minh Pham, Jeffrey A Zonder, Q Ping Dou
Introduction- Mantle cell lymphoma (MCL) is an incurable, often aggressive B-cell malignancy. Bortezomib (BTZ), the 20S proteasome inhibitor was originally developed and approved for treatment of relapsed refractory multiple myeloma, and subsequently approved for treatment of MCL. BTZ's single-agent activity induces clinical responses in approximately one-third of relapsed MCL patients. BTZ-containing combination therapies have further improved the quality and duration of clinical responses compared to standard chemotherapies in previously untreated MCL patients...
December 3, 2016: Expert Opinion on Drug Discovery
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