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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...
July 23, 2016: Journal of Autoimmunity
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
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
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
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
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
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
Giuseppe Lucarelli, Monica Rutigliano, Francesca Sanguedolce, Vanessa Galleggiante, Andrea Giglio, Simona Cagiano, Pantaleo Bufo, Eugenio Maiorano, Domenico Ribatti, Elena Ranieri, Margherita Gigante, Loreto Gesualdo, Matteo Ferro, Ottavio de Cobelli, Carlo Buonerba, Giuseppe Di Lorenzo, Sabino De Placido, Silvano Palazzo, Carlo Bettocchi, Pasquale Ditonno, Michele Battaglia
Glucose-6-phosphate isomerase (GPI), also known as phosphoglucose isomerase, was initially identified as the second glycolytic enzyme that catalyzes the interconversion of glucose-6-phosphate to fructose-6-phosphate. Later studies demonstrated that GPI was the same as the autocrine motility factor (AMF), and that it mediates its biological effects through the interaction with its surface receptor (AMFR/gp78). In this study, we assessed the role of GPI/AMF as a prognostic factor for clear cell renal cell carcinoma (ccRCC) cancer-specific (CSS) and progression-free survival (PFS)...
November 2015: Medicine (Baltimore)
Kang Tian, Weiliang Zhong, Xifu Zheng, Jinrui Zhang, Pixu Liu, Weiguo Zhang, Han Liu
Cartilage defect is an intractable clinical problem. Therapeutic strategies for cartilage repair are far from optimal due to poor proliferation capacity of chondrocytes. Autologous chondrocyte implantation is a cell based therapy that uses in vitro amplified healthy chondrocytes from the patient. However, chondrocyte dedifferentiation during in vitro culture limits its application. Neuroleukin (NLK) is a multifunctional protein that stimulates cell growth and migration, together with its receptor autocrine motility factor receptor (AMFR, also called gp78)...
2015: Scientific Reports
Ting Zhang, Yue Xu, Yanfen Liu, Yihong Ye
Eukaryotic cells eliminate misfolded proteins from the endoplasmic reticulum (ER) via a conserved process termed ER-associated degradation (ERAD). Central regulators of the ERAD system are membrane-bound ubiquitin ligases, which are thought to channel misfolded proteins through the ER membrane during retrotranslocation. Hrd1 and gp78 are mammalian ubiquitin ligases homologous to Hrd1p, an ubiquitin ligase essential for ERAD in Saccharomyces cerevisiae. However, the functional relevance of these proteins to Hrd1p is unclear...
December 1, 2015: Molecular Biology of the Cell
Lei Li, Guang Gao, Jay Shankar, Bharat Joshi, Leonard J Foster, Ivan R Nabi
Gp78 is an ERAD-associated E3 ubiquitin ligase that induces degradation of the mitofusin mitochondrial fusion proteins and mitochondrial fission. Gp78 is localized throughout the ER; however, the anti-Gp78 3F3A monoclonal antibody (mAb) recognizes Gp78 selectively in mitochondria-associated ER domains. Epitope mapping localized the epitope of 3F3A and a commercial anti-Gp78 mAb to an 8-amino acid motif (533-541) in mouse Gp78 isoform 2 that forms part of a highly conserved 41-amino acid region containing 14-3-3- and WW-binding domains and a p38 MAP kinase (p38 MAPK) consensus site on Ser-538 (S538)...
November 1, 2015: Molecular Biology of the Cell
Jin Chai, Shi-Ying Cai, Xiaocong Liu, Wei Lian, Sheng Chen, Liangjun Zhang, Xinchan Feng, Ying Cheng, Xiaochong He, Yu He, Lei Chen, Rongquan Wang, Huaizhi Wang, James L Boyer, Wensheng Chen
BACKGROUND & AIMS: Multidrug resistance-associated protein 2 (MRP2) excretes conjugated organic anions including bilirubin and bile acids. Malfunction of MRP2 leads to jaundice in patients. Studies in rodents indicate that Radixin plays a critical role in determining Mrp2 canalicular membrane expression. However, it is not known how human hepatic MRP2 expression is regulated in cholestasis. METHODS: We assessed liver MRP2 expression in patients with obstructive cholestasis caused by gallstone blockage of bile ducts, and investigated the regulatory mechanism in HepG2 cells...
December 2015: Journal of Hepatology
(no author information available yet)
No abstract text is available yet for this article.
2015: Lipids in Health and Disease
Katsunori Nonogaki, Tomoe Yamazaki, Mari Murakami, Takao Kaji
Fibroblast growth factor (FGF) 21 is a mediator of glucose and lipid metabolism. Although exogenous administration of FGF21 exerts beneficial effects on glucose and lipid metabolism, circulating FGF21 levels are elevated in ob/ob and db/db mice, diet-induced obese mice and obese human. Here we show that ingestion of eicosapentaenoic acid (EPA) for 6 days after individually-housing significantly suppressed the hyperglycemia and hypertriglyceridemia associated with decreases in plasma insulin and FGF21 levels in KKA(y) mice while having no effects on food intake, body weight or plasma active GLP-1 levels...
August 21, 2015: Biochemical and Biophysical Research Communications
Y-W Chang, C-F Tseng, M-Y Wang, W-C Chang, C-C Lee, L-T Chen, M-C Hung, J-L Su
Heat-shock protein 5 (HSPA5) is a marker for poor prognosis in breast cancer patients and has an important role in cancer progression, including promoting drug resistance and metastasis. In this study, we identify that the specific lysine residue 447 (K447) of HSPA5 could be modified with polyubiquitin for subsequent degradation through the ubiquitin proteasomal system, leading to the suppression of cell migration and invasion of breast cancer. We further found that GP78, an E3 ubiquitin ligase, interacted with the C-terminal region of HSPA5 and mediated HSPA5 ubiquitination and degradation...
March 24, 2016: Oncogene
Peter T C Wang, Pierre O Garcin, Min Fu, Matthew Masoudi, Pascal St-Pierre, Nelly Panté, Ivan R Nabi
Gp78 (also known as AMFR), an endoplasmic-reticulum (ER)-associated protein degradation (ERAD) E3 ubiquitin ligase, localizes to mitochondria-associated ER and targets the mitofusin (Mfn1 and Mfn2) mitochondrial fusion proteins for degradation. Gp78 is also the cell surface receptor for autocrine motility factor (AMF), which prevents Gp78-dependent mitofusin degradation. Gp78 ubiquitin ligase activity promotes ER-mitochondria association and ER-mitochondria Ca(2+) coupling, processes that are reversed by AMF...
August 1, 2015: Journal of Cell Science
Tianpeng Zhang, Dhong Hyo Kho, Ying Wang, Yosuke Harazono, Kosei Nakajima, Youming Xie, Avraham Raz
Nonalcoholic steatohepatitis (NASH) is related to metabolic dysregulation and the perturbation of endoplasmic reticulum (ER) homeostasis that frequently develops into hepatocellular carcinoma (HCC). Gp78 is E3 ligase, which regulates endoplasmic reticulum-associated degradation (ERAD) by ubiquitinylation of misfolded ER proteins. Here, we report that upon ageing (12 months), gp78-/- mice developed obesity, recapitulating age-related human NASH. Liver histology of gp78-/- mice revealed typical steatosis, hepatic inflammation and fibrosis, followed by progression to hepatocellular tumors...
2015: PloS One
YongQiang Wang, Sung-Mi Kim, Michael J Trnka, Yi Liu, A L Burlingame, Maria Almira Correia
CYP3A4 is an abundant and catalytically dominant human liver endoplasmic reticulum-anchored cytochrome P450 enzyme engaged in the biotransformation of endo- and xenobiotics, including >50% of clinically relevant drugs. Alterations of CYP3A4 protein turnover can influence clinically relevant drug metabolism and bioavailability and drug-drug interactions. This CYP3A4 turnover involves endoplasmic reticulum-associated degradation via the ubiquitin (Ub)-dependent 26 S proteasomal system that relies on two highly complementary E2 Ub-conjugating-E3 Ub-ligase (UBC7-gp78 and UbcH5a-C terminus of Hsc70-interacting protein (CHIP)-Hsc70-Hsp40) complexes, as well as protein kinases (PK) A and C...
February 6, 2015: Journal of Biological Chemistry
Weixiao Liu, Yongliang Shang, Wei Li
The modification of proteins with polyubiquitin chains alters their stability, localization and activity, thus regulating various aspects of cellular functions in eukaryotic cells. The ER quality control protein E3 gp78 catalyzes Lys48-linked polyubiquitin-chain- assembly on the Ube2g2 active site and is capable of transferring preassembled ubiquitin chains to its substrates. However, the underlying mechanism of polyubiquitin- chain-assembly remains elusive. Here, we demonstrate that the active site-linked ubiquitin chain is extended from the distal end by the cooperative actions of the G2BR and CUE domains of gp78...
2014: Scientific Reports
Taichi Hara, Yukiko Hashimoto, Tomoko Akuzawa, Rika Hirai, Hisae Kobayashi, Ken Sato
Peripheral myelin protein 22 (PMP22) resides in the plasma membrane and is required for myelin formation in the peripheral nervous system. Many PMP22 mutants accumulate in excess in the endoplasmic reticulum (ER) and lead to the inherited neuropathies of Charcot-Marie-Tooth (CMT) disease. However, the mechanism through which PMP22 mutants accumulate in the ER is unknown. Here, we studied the quality control mechanisms for the PMP22 mutants L16P and G150D, which were originally identified in mice and patients with CMT...
2014: Scientific Reports
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