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https://www.readbyqxmd.com/read/28759037/role-of-hspa1l-as-a-cellular-prion-protein-stabilizer-in-tumor-progression-via-hif-1%C3%AE-gp78-axis
#1
J H Lee, Y-S Han, Y M Yoon, C W Yun, S P Yun, S M Kim, H Y Kwon, D Jeong, M J Baek, H J Lee, S-J Lee, H J Han, S H Lee
The cellular prion protein (PrP(C)) is associated with metastasis, tumor progression and recurrence; however, the precise mechanisms underlying its action is not well understood. Our study found that PrP(C) degradation decreased tumor progression in colorectal cancer (CRC). In a CRC cell line and human CRC tissue exposed to hypoxia, induced heat-shock 70-kDa protein-1-like (HSPA1L) expression stabilized hypoxia-inducible factor-1α (HIF-1α) protein and promoted PrP(C) accumulation and tumorigenicity in vivo...
July 31, 2017: Oncogene
https://www.readbyqxmd.com/read/28656280/role-of-glycoprotein-78-and-cidec-in-hepatic-steatosis
#2
Jie Li, Guocai Liu, Feng Zhang, Zhiwen Zhang, Yuqiao Xu, Qing Li
Hepatic glycoprotein (gp78), a membrane-anchored E3 ubiquitin ligase, has been reported to be involved in regulating lipid and energy metabolism in animals, and cell death‑inducing DFFA‑like effector c (cidec) has emerged as an important regulator of metabolism, which has been implicated in the process of fat differentiation. Nonalcoholic fatty liver disease is a metabolic disorder associated with hepatic steatosis. In the present study, to investigate the role of gp78 and cidec in hepatic steatosis, an in vitro cell culture model of hepatic steatosis was established, using the AML12 mouse hepatocyte cell line to assess the protein expression of gp78...
August 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28604676/cholesterol-and-fatty-acids-regulate-cysteine-ubiquitylation-of-acat2-through-competitive-oxidation
#3
Yong-Jian Wang, Yan Bian, Jie Luo, Ming Lu, Ying Xiong, Shu-Yuan Guo, Hui-Yong Yin, Xu Lin, Qin Li, Catherine C Y Chang, Ta-Yuan Chang, Bo-Liang Li, Bao-Liang Song
Ubiquitin linkage to cysteine is an unconventional modification targeting protein for degradation. However, the physiological regulation of cysteine ubiquitylation is still mysterious. Here we found that ACAT2, a cellular enzyme converting cholesterol and fatty acid to cholesteryl esters, was ubiquitylated on Cys277 for degradation when the lipid level was low. gp78-Insigs catalysed Lys48-linked polyubiquitylation on this Cys277. A high concentration of cholesterol and fatty acid, however, induced cellular reactive oxygen species (ROS) that oxidized Cys277, resulting in ACAT2 stabilization and subsequently elevated cholesteryl esters...
July 2017: Nature Cell Biology
https://www.readbyqxmd.com/read/28552883/sel1l-dependent-substrates-require-derlin2-3-and-herp1-2-for-endoplasmic-reticulum-associated-degradation
#4
Takehiro Sugimoto, Satoshi Ninagawa, Shimpei Yamano, Tokiro Ishikawa, Tetsuya Okada, Shunichi Takeda, Kazutoshi Mori
Accumulation of unfolded/misfolded proteins in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR). The ATF6 pathway is one of the three major pathways in vertebrates. Although ATF6, a transmembrane-type glycoprotein in the ER, functions as a UPR sensor/transducer, it is an unstable protein with a half-life of approximately 2 h and is constitutively subjected to the ER-associated degradation system with the location of the misfolded part in the ER lumen (ERAD-L). ERAD-L substrates are delivered to the cytosol through the retrotranslocon, which likely contains HRD1 (E3), gp78 (E3), SEL1L (a partner of HRD1), Derlin1/2/3 and Herp1/2...
May 26, 2017: Cell Structure and Function
https://www.readbyqxmd.com/read/28536268/endoplasmic-reticulum-stress-induced-degradation-of-dnajb12-stimulates-bok-accumulation-and-primes-cancer-cells-for-apoptosis
#5
Pattarawut Sopha, Hong Yu Ren, Diane E Grove, Douglas M Cyr
DNAJB12 (JB12) is an endoplasmic reticulum (ER)-associated Hsp40 family protein that recruits Hsp70 to the ER surface to coordinate the function of ER-associated and cytosolic chaperone systems in protein quality control. Hsp70 is stress-inducible, but paradoxically, we report here that JB12 was degraded by the proteasome during severe ER stress. Destabilized JB12 was degraded by ER-associated degradation complexes that contained HERP, Sel1L, and gp78. JB12 was the only ER-associated chaperone that was destabilized by reductive stress...
July 14, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28528366/cdk5-mediated-phosphorylation-dependent-ubiquitination-and-degradation-of-e3-ubiquitin-ligases-gp78-accelerates-neuronal-death-in-parkinson-s-disease
#6
Qingzhi Wang, Fengjuan Jiao, Pei Zhang, Jianguo Yan, Zheng Zhang, Feng He, Qian Zhang, Zexi Lv, Xiang Peng, Hongwei Cai, Bo Tian
The molecular mechanisms responsible for the loss of dopaminergic neurons in Parkinson's disease (PD) remain obscure. Loss of function of E3 ubiquitin ligases is associated with mitochondria dysfunction, dysfunction of protein degradation, and α-synuclein aggregation, which are major contributors to neurodegeneration in PD. Recent research has thus focused on E3 ubiquitin ligase glycoprotein 78 (GP78); however, the role of GP78 in PD pathogenesis remains unclear. Notably, cyclin-dependent kinase 5 (CDK5) controls multiple cellular events in postmitotic neurons, and CDK5 activity has been implicated in the pathogenesis of PD...
May 20, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/28518143/calcium-sensing-receptor-protects-high-glucose-induced-energy-metabolism-disorder-via-blocking-gp78-ubiquitin-proteasome-pathway
#7
Yuehong Wang, Ping Gao, Can Wei, Hongzhu Li, Li Zhang, Yajun Zhao, Bo Wu, Ye Tian, Weihua Zhang, Lingyun Wu, Rui Wang, Changqing Xu
Diabetic cardiomyopathy (DCM) is a major complication and fatal cause of the patients with diabetes. The calcium sensing receptor (CaSR) is a G protein-coupled receptor, which is involved in maintaining calcium homeostasis, regulating cell proliferation and apoptosis, and so on. In our previous study, we found that CaSR expression, intracellular calcium levels and cardiac function were all significantly decreased in DCM rats; however, the exact mechanism are not clear yet. The present study revealed the protective role of CaSR in myocardial energy metabolism disorder induced by high glucose (HG) as well as the underlying mechanism...
May 18, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28434917/conformational-dynamics-and-allostery-in-e2-e3-interactions-drive-ubiquitination-gp78-and-ube2g2
#8
Kalyan S Chakrabarti, Jess Li, Ranabir Das, R Andrew Byrd
Conformational dynamics plays a fundamental role in molecular recognition and activity in enzymes. The ubiquitin-conjugating enzyme (E2) Ube2g2 functions with the ubiquitin ligase (E3) gp78 to assemble poly-ubiquitin chains on target substrates. Two domains in gp78, RING and G2BR, bind to two distant regions of Ube2g2, and activate it for ubiquitin (Ub) transfer. G2BR increases the affinity between the RING and Ube2g2 by 50-fold, while the RING catalyzes the transfer of Ub from the Ube2g2∼Ub conjugate. How G2BR and RING activate Ube2g2 is unclear...
May 2, 2017: Structure
https://www.readbyqxmd.com/read/28301499/svip-regulates-z-variant-alpha-1-antitrypsin-retro-translocation-by-inhibiting-ubiquitin-ligase-gp78
#9
Nazli Khodayari, Rejean Liqun Wang, George Marek, Karina Krotova, Mariana Kirst, Chen Liu, Farshid Rouhani, Mark Brantly
Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by early-onset emphysema and liver disease. The most common disease-causing mutation is a single amino acid substitution (Glu/Lys) at amino acid 342 of the mature protein, resulting in disruption of the 290-342 salt bridge (an electrophoretic abnormality defining the mutation [Z allele, or ZAAT]), protein misfolding, polymerization, and accumulation in the endoplasmic reticulum of hepatocytes and monocytes. The Z allele causes a toxic gain of function, and the E3 ubiquitin ligase gp78 promotes degradation and increased solubility of endogenous ZAAT...
2017: PloS One
https://www.readbyqxmd.com/read/28285986/calcium-dependent-regulation-of-protein-ubiquitination-interplay-between-e3-ligases-and-calcium-binding-proteins
#10
REVIEW
Rukmini Mukherjee, Aneesha Das, Saikat Chakrabarti, Oishee Chakrabarti
The ubiquitination status of proteins and intracellular calcium levels are two factors which keep changing inside any living cell. These two events appear to be independent of each other but recent experimental evidences show that ubiquitination of cellular proteins are influenced by calcium, Calmodulin, Calmodulin-dependent kinase II and other proteins of calcium dependent pathways. E3 ligases like Nedd4, SCF complex, APC, GP78 and ITCH are important regulators of calcium mediated processes. A bioinformatics analysis to inspect sequences and interacting partners of 242 candidate E3 ligases show the presence of calcium and/or Calmodulin binding motifs/domains within their sequences...
March 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28212872/correlation-between-gp78-gene-polymorphism-and-coronary-atherosclerotic-heart-disease
#11
Long Wang, Hua-Cheng Li, Jian Zhou, Bo Yang, Cheng-Dong Qiao, Yong-Ming Liu, Zheng Zhang
OBJECTIVE: To study the correlation between GP78 gene polymorphism and blood fat, blood glucose, blood pressure as well as coronary atherosclerotic heart disease. METHODS: 72 patients with coronary atherosclerotic heart disease were selected as the observation group. 68 healthy participants were selected as the control group. The gp78 gene polymorphism of both groups was studied by the method of polymerase chain reaction-restriction fragment length polymorphism (RFLP)...
February 14, 2017: Hellenic Journal of Cardiology: HJC, Hellēnikē Kardiologikē Epitheōrēsē
https://www.readbyqxmd.com/read/28091582/androgen-mediated-regulation-of-endoplasmic-reticulum-associated-degradation-and-its-effects-on-prostate-cancer
#12
Yalcin Erzurumlu, Petek Ballar
The endoplasmic reticulum (ER) comprises thirty percent of the newly translated proteins in eukaryotic cells. The quality control mechanism within the ER distinguishes between properly and improperly folded proteins and ensures that unwanted proteins are retained in the ER and subsequently degraded through ER-associated degradation (ERAD). Besides cleaning of misfolded proteins ERAD is also important for physiological processes by regulating the abundance of normal proteins of the ER. Thus it is important to unreveal the regulation patterns of ERAD...
January 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28027595/inhibition-of-the-sterol-regulatory-element-binding-protein-pathway-suppresses-hepatocellular-carcinoma-by-repressing-inflammation-in-mice
#13
Na Li, Zhang-Sen Zhou, Yang Shen, Jie Xu, Hong-Hua Miao, Ying Xiong, Feng Xu, Bo-Liang Li, Jie Luo, Bao-Liang Song
Obesity is a critical risk factor for hepatocellular carcinoma (HCC). However, it remains unknown whether inhibition of de novo lipid biosynthesis can suppress HCC. In this study, we blocked the sterol regulatory element-binding protein (SREBP) pathway, one of the key determinants of lipid homeostasis, by ablating 78-kDa cell-surface glycoprotein or SREBP cleavage-activating protein in hepatocytes, as well as by administering a chemical compound called betulin. We found that either genetically or pharmacologically inhibiting the SREBP pathway dramatically reduced diethylnitrosamine-induced HCC progression by down-regulating tumor-promoting cytokines, including interleukin (IL)-6, tumor necrosis factor alpha, and IL-1β...
June 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/27461470/pro-inflammatory-cytokines-enhance-erad-and-atf6%C3%AE-pathway-activity-in-salivary-glands-of-sj%C3%A3-gren-s-syndrome-patients
#14
María-José Barrera, Sergio Aguilera, Isabel Castro, Juan Cortés, Verónica Bahamondes, Andrew F G Quest, Claudio Molina, Sergio González, Marcela Hermoso, Ulises Urzúa, Cecilia Leyton, María-Julieta González
Salivary gland (SG) acinar-cells are susceptible to endoplasmic reticulum (ER) stress related to their secretory activity and the complexity of synthesized secretory products. SGs of Sjögren's syndrome patients (SS)-patients show signs of inflammation and altered proteostasis, associated with low IRE1α/XBP-1 pathway activity without avert increases in apoptosis. Acinar-cells may avoid apoptosis by activation of the ATF6α pathway and ER-associated protein degradation (ERAD). The aim of this study was to evaluate the role of pro-inflammatory cytokines in ATF6α pathway/ERAD activation and cell viability in labial salivary glands (LSG) of SS-patients...
December 2016: Journal of Autoimmunity
https://www.readbyqxmd.com/read/27407164/structural-insights-into-the-interaction-of-p97-n-terminus-domain-and-vbm-in-rhomboid-protease-rhbdl4
#15
Jia Jia Lim, Youngjin Lee, Tue Tu Ly, Jung Youn Kang, Jung-Gyu Lee, Jun Yop An, Hyung-Seop Youn, Kyoung Ryoung Park, Tae Gyun Kim, Jin Kuk Yang, Youngsoo Jun, Soo Hyun Eom
RHBDL4 is an active rhomboid that specifically recognizes and cleaves atypical, positively charged transmembrane endoplasmic reticulum-associated degradation (ERAD) substrates. Interaction of valosin-containing protein (p97/VCP) and RHBDL4 is crucial to retrotranslocate polyubiquitinated substrates for ERAD pathway. Here, we report the first complex structure of VCP-binding motif (VBM) with p97 N-terminal domain (p97N) at 1.88 Å resolution. Consistent with p97 adaptor proteins including p47-ubiquitin regulatory X (UBX), gp78-VCP-interacting motif (VIM), OTU1-UBX-like element, and FAF1-UBX, RHBDL4 VBM also binds at the interface between the two lobes of p97N...
September 15, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27387505/lunapark-is-a-component-of-a-ubiquitin-ligase-complex-localized-to-the-endoplasmic-reticulum-three-way-junctions
#16
Yupeng Zhao, Ting Zhang, Huanhuan Huo, Yihong Ye, Yanfen Liu
The endoplasmic reticulum (ER) network comprises sheets and tubules that are connected by dynamic three-way junctions. Lunapark (Lnp) localizes to and stabilizes ER three-way junctions by antagonizing the small GTPase Atlastin, but how Lnp shapes the ER network is unclear. Here, we used an affinity purification approach and mass spectrometry to identify Lnp as an interacting partner of the ER protein quality control ubiquitin ligase gp78. Accordingly, Lnp purified from mammalian cells has a ubiquitin ligase activity in vitro Intriguingly, biochemical analyses show that this activity can be attributed not only to associated ubiquitin ligase, but also to an intrinsic ubiquitin ligase activity borne by Lnp itself...
August 26, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27320797/hepatic-cytochromes-p450-structural-degrons-and-barcodes-posttranslational-modifications-and-cellular-adapters-in-the-erad-endgame
#17
Sung-Mi Kim, YongQiang Wang, Noushin Nabavi, Yi Liu, Maria Almira Correia
The endoplasmic reticulum (ER)-anchored hepatic cytochromes P450 (P450s) are enzymes that metabolize endo- and xenobiotics i.e. drugs, carcinogens, toxins, natural and chemical products. These agents modulate liver P450 content through increased synthesis or reduction via inactivation and/or proteolytic degradation, resulting in clinically significant drug-drug interactions. P450 proteolytic degradation occurs via ER-associated degradation (ERAD) involving either of two distinct routes: Ubiquitin (Ub)-dependent 26S proteasomal degradation (ERAD/UPD) or autophagic lysosomal degradation (ERAD/ALD)...
August 2016: Drug Metabolism Reviews
https://www.readbyqxmd.com/read/27067047/the-linkage-specificity-determination-of-ube2g2-gp78-mediated-polyubiquitination
#18
Fengyi Gao, Yongliang Shang, Weixiao Liu, Wei Li
Polyubiquitin chain linkage specificity or topology is essential for its role in diverse cellular processes. Previous studies pay more attentions to the linkage specificity of the first ubiquitin moieties, whereas, little is known about the editing mechanism of linkage specificity in longer polyubiquitin chains. gp78 and its cognate E2-Ube2g2 catalyze lysine48 (K48)-linked polyubiquitin chains to promote the degradation of targeted proteins. Here, we show that the linkage specificity of the entire polyubiquitin chain is determined by the conjugation manner of the first ubiquitin molecule but not the following ones...
May 13, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/26949185/bok-is-a-non-canonical-bcl-2-family-effector-of-apoptosis-regulated-by-er-associated-degradation
#19
Fabien Llambi, Yue-Ming Wang, Bernadette Victor, Mao Yang, Desiree M Schneider, Sébastien Gingras, Melissa J Parsons, Janet H Zheng, Scott A Brown, Stéphane Pelletier, Tudor Moldoveanu, Taosheng Chen, Douglas R Green
The mitochondrial pathway of apoptosis is initiated by mitochondrial outer membrane permeabilization (MOMP). The BCL-2 family effectors BAX and BAK are thought to be absolutely required for this process. Here, we report that BCL-2 ovarian killer (BOK) is a bona fide yet unconventional effector of MOMP that can trigger apoptosis in the absence of both BAX and BAK. However, unlike the canonical effectors, BOK appears to be constitutively active and unresponsive to antagonistic effects of the antiapoptotic BCL-2 proteins...
April 7, 2016: Cell
https://www.readbyqxmd.com/read/26743086/ubiquitin-mediated-regulation-of-the-e3-ligase-gp78-by-mgrn1-in-trans-affects-mitochondrial-homeostasis
#20
Rukmini Mukherjee, Oishee Chakrabarti
Cellular quality control provides an efficient surveillance system to regulate mitochondrial turnover. This study elucidates a new interaction between the cytosolic E3 ligase mahogunin RING finger 1 (MGRN1) and the endoplasmic reticulum (ER) ubiquitin E3 ligase GP78 (also known as AMFR). Loss of Mgrn1 function has been implicated in late-onset spongiform neurodegeneration and congenital heart defects, among several developmental defects. Here, we show that MGRN1 ubiquitylates GP78 in trans through non-canonical K11 linkages...
February 15, 2016: Journal of Cell Science
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