scholarly journals The Type II Deiodinase Is Retrotranslocated to the Cytoplasm and Proteasomes via p97/Atx3 Complex

2013 ◽  
Vol 27 (12) ◽  
pp. 2105-2115 ◽  
Author(s):  
Rafael Arrojo e Drigo ◽  
Péter Egri ◽  
Sungro Jo ◽  
Balázs Gereben ◽  
Antonio C. Bianco
Keyword(s):  
Molecular Weight ◽  
Endoplasmic Reticulum ◽  
Thyroid Hormone ◽  
High Molecular Weight ◽  
20S Proteasome ◽  
Type I ◽  
Type Ii ◽  
Cell Models ◽  
Natural Substrate ◽  
Iodothyronine Deiodinase

The type II iodothyronine deiodinase (D2) is a type I endoplasmic reticulum (ER)-resident thioredoxin fold-containing selenoprotein that activates thyroid hormone. D2 is inactivated by ER-associated ubiquitination and can be reactivated by two ubiquitin-specific peptidase-class D2-interacting deubiquitinases (DUBs). Here, we used D2-expressing cell models to define that D2 ubiquitination (UbD2) occurs via K48-linked ubiquitin chains and that exposure to its natural substrate, T4, accelerates UbD2 formation and retrotranslocation to the cytoplasm via interaction with the p97-ATPase complex. D2 retrotranslocation also includes deubiquitination by the p97-associated DUB Ataxin-3 (Atx3). Inhibiting Atx3 with eeyarestatin-I did not affect D2:p97 binding but decreased UbD2 retrotranslocation and caused ER accumulation of high-molecular weight UbD2 bands possibly by interfering with the D2-ubiquitin-specific peptidases binding. Once in the cytosol, D2 is delivered to the proteasomes as evidenced by coprecipitation with 19S proteasome subunit S5a and increased colocalization with the 20S proteasome. We conclude that interaction between UbD2 and p97/Atx3 mediates retranslocation of UbD2 to the cytoplasm for terminal degradation in the proteasomes, a pathway that is accelerated by exposure to T4.

Carbon Fibre Reinforced Ultra-High Molecular Weight Polyethylene for Medical Application

1977 ◽  
Vol 6 (4) ◽  
pp. 123-124 ◽  
Author(s):  
J S Bradley ◽  
E J Evans
Keyword(s):  
Molecular Weight ◽  
Composite Material ◽  
High Molecular Weight ◽  
Medical Application ◽  
Flexural Properties ◽  
Type I ◽  
Type Ii ◽  
Carbon Fibres ◽  
Compression Moulding ◽  
Ultra High Molecular Weight

Ultra-high molecular weight polyethylene (UHMWPE) has been reinforced with type I and type II carbon fibres by a compression moulding technique. The composite is found to have markedly improved tensile and flexural properties, suggesting that it would be useful both as an improvement to current polyethylene components and as an inducement to more elaborate designs using the composite material.

scholarly journals Fibronectin-independent adhesion of fibroblasts to the extracellular matrix: mediation by a high molecular weight membrane glycoprotein.

1981 ◽  
Vol 91 (3) ◽  
pp. 647-653 ◽  
Author(s):  
P A Harper ◽  
R L Juliano
Keyword(s):  
Molecular Weight ◽  
Extracellular Matrix ◽  
High Molecular Weight ◽  
Cho Cells ◽  
Matrix Material ◽  
Differential Sensitivity ◽  
Galactose Oxidase ◽  
Membrane Glycoprotein ◽  
Type I ◽  
Type Ii

Fibroblastic CHO cells readily adhere to fibronectin (Fn) coated substrata. From the parental cell population we have recently selected a series of adhesion variants (ADV cells) that cannot adhere to Fn substrata (Harper and Juliano. 1980. J. Cell. Biol. 87:755-763). However, ADV cells readily adhere to substrata coated with extracellular matrix material (ECM) derived from human diploid fibroblasts by a mechanism that does not involve fibronectin (Harper and Juliano. 1981. Nature (Lond.). 290:136-138). Te Fn-dependent adhesion mechanism of parental cells (type 1 adhesion) and the ECM-dependent adhesion of ADV cells (type II adhesion) can also be discriminated on the basis of their differential sensitivity to proteolysis, with the type II mechanism being far more sensitive. In this communication we report that parental CHO cells possess both type I and type II mechanisms whereas ADV cells possess only the type II mechanism. We also identify a high molecular weight membrane glycoprotein (gp 265) that seems to play a role in type II adhesion. This component is detected by [125I]lactoperoxidase of [3H]borohydride-galactose oxidase labeling of surface proteins in WT and AD cells. Cleavage of gp 265 with low doses of proteases correlates completely with the loss of type II adhesion capacity. Thus CHO cells possess two functionally and biochemically distinct adhesion mechanisms, one involving exogenous Fn and the other mediated by the membrane component gp 265.

Effects of 5,5′-diphenylhydantoin on the thyroid status in rats

1996 ◽  
Vol 134 (2) ◽  
pp. 221-224 ◽  
Author(s):  
JP Schröder-van der Elst ◽  
D van der Heide ◽  
C van der Bent ◽  
E Kaptein ◽  
TJ Visser ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Metabolic Diseases ◽  
University Hospital ◽  
Pituitary Hormone ◽  
Type I ◽  
Uridine Diphosphate ◽  
Type Ii ◽  
Thyroid Status ◽  
Iodothyronine Deiodinase ◽  
Total Body Oxygen

Schröder-van der Elst JP, van der Heide D, van der Bent C, Kaptein E, Visser TJ, DiStefano JJ, Effects of 5,5′diphenylhydantoin on the thyroid status in rats. Eur J Endocrinol 1996;134:221–4. ISSN 0804–4643 Treatment of rats with phenytoin (DPH), an anti-epileptic drug, results in lower tissue thyroid hormone (TH) levels. To investigate if this is accompanied by tissue hypothyroidism, rats were treated for 3 weeks with DPH (50 mg/kg body wt in food). Thyroid hormone-dependent parameters were measured, and the results were compared to those of control rats and to those of athyreotic rats substituted with thyroxine + triiodothyronine (Tx + TH) to reach the same plasma TH levels as DPH-treated rats. These rats were mildly hypothyroid with regard to their TH and TSH levels and TH-dependent parameters. Both DPH and Tx + TH led to a decrease in plasma thyroxine (T4) and triiodothyronine (T3) (±70% of the control). The percentage free T4 was unchanged. Plasma thyrotropin (TSH) was increased only in the Tx + TH rats (sixfold). For DPH rats, pituitary hormone content was not different from the control; growth hormone was lower and TSH was higher in Tx + TH rats. In DPH and Tx + TH rats, an increase in hepatic T4 and T3 uridine-diphosphate glucuronyltransferase activity was found, likewise indicating a change in the metabolic pathway of TH. Hepatic iodothyronine deiodinase (ID) type I activity decreased in Tx + TH rats but did not alter in DPH rats. Hepatic α-glycerophosphate dehydrogenase (α-GPD) decreased in DPH and Tx + TH rats. Malic enzyme in liver was enhanced in DPH rats. In the brains of DPH rats the level of α-GPD activity was raised; in Tx + TH it was lowered. The ID type II activity in the brain was reduced in DPH rats, but ID type III did not change for either group. Total body oxygen consumption increased in DPH rats (13%); it decreased in Tx + TH rats (9%). Our results show that DPH causes changes comparable to mild hypothyroidism. The lack of or a diminished hypothyroid response can be explained as the attenuating agonistic effect of DPH, which is supported by O2 consumption, brain ID type II and α-GPD activities. The T4 content was reduced by 30% in thyroid digests; this, together with a reduced T4 secretion, can lead to serious hypothyroxinemia during prolonged DPH treatment. JP Schröder-van der Elst, Department of Metabolic Diseases and Endocrinology, Building 1, C4-R, University Hospital, Rijnsburgerweg 10, 2300 RC Leiden, The Netherlands

scholarly journals Inhibition of type I and type II iodothyronine deiodinase activity in rat liver, kidney and brain produced by selenium deficiency

1989 ◽  
Vol 259 (3) ◽  
pp. 887-892 ◽  
Author(s):  
G J Beckett ◽  
D A MacDougall ◽  
F Nicol ◽  
J R Arthur
Keyword(s):  
Body Weight ◽  
Thyroid Hormone ◽  
Feedback Inhibition ◽  
Selenium Deficiency ◽  
Stress Factors ◽  
Type I ◽  
Type Ii ◽  
Hormone Metabolism ◽  
Iodothyronine Deiodinase ◽  
Thyroid Hormone Metabolism

Selenium deficiency for periods of 5 or 6 weeks in rats produced an inhibition of tri-iodothyronine (T3) production from added thyroxine (T4) in brain, liver and kidney homogenate. This inhibition was reflected in plasma T4 and T3 concentrations, which were respectively increased and decreased in selenium-deficient animals. Although plasma T4 levels increased in selenium-deficient animals, this did not produce the normal feedback inhibition on thyrotropin release from the pituitary. Selenium deficiency was confirmed in the animals by decreased selenium-dependent glutathione peroxidase (Se-GSH-Px) activity in all of these tissues. Administration of selenium, as a single intraperitoneal injection of 200 micrograms of selenium (as Na2SeO3)/kg body weight completely reversed the effects of selenium deficiency on thyroid-hormone metabolism and partly restored the activity of Se-GSH-Px. Selenium administration at 10 micrograms/kg body weight had no significant effect on thyroid-hormone metabolism or on Se-GSH-Px activity in any of the tissues studied. The characteristic changes in plasma thyroid-hormone levels that occurred in selenium deficiency appeared not to be due to non-specific stress factors, since food restriction to 75% of normal intake or vitamin E deficiency produced no significant changes in plasma T4 or T3 concentration. These data are consistent with the view that the Type I and Type II iodothyronine deiodinase enzymes are seleno-enzymes or require selenium-containing cofactors for activity.

Labelling of non-A, non-B hepatitis infected chimpanzee hepatocytes with nuclease-gold conjugates

1984 ◽  
Vol 42 ◽  
pp. 250-251
Author(s):  
G. D. Gagne ◽  
M. F. Miller ◽  
D. A. Peterson
Keyword(s):  
Endoplasmic Reticulum ◽  
Experimental Infection ◽  
Uranyl Acetate ◽  
Type I ◽  
Cellular Injury ◽  
Type Ii ◽  
Tubular Structures ◽  
Type Iii ◽  
Type Iv ◽  
Infected Chimpanzee

Experimental infection of chimpanzees with non-A, non-B hepatitis (NANB) or with delta agent hepatitis results in the appearance of characteristic cytoplasmic alterations in the hepatocytes. These alterations include spongelike inclusions (Type I), attached convoluted membranes (Type II), tubular structures (Type III), and microtubular aggregates (Type IV) (Fig. 1). Type I, II and III structures are, by association, believed to be derived from endoplasmic reticulum and may be morphogenetically related. Type IV structures are generally observed free in the cytoplasm but sometimes in the vicinity of type III structures. It is not known whether these structures are somehow involved in the replication and/or assembly of the putative NANB virus or whether they are simply nonspecific responses to cellular injury. When treated with uranyl acetate, type I, II and III structures stain intensely as if they might contain nucleic acids. If these structures do correspond to intermediates in the replication of a virus, one might expect them to contain DNA or RNA and the present study was undertaken to explore this possibility.

Regulation of Mammary Gland Sensitivity to Thyroid Hormones During the Transition from Pregnancy to Lactation

2008 ◽  
Vol 233 (10) ◽  
pp. 1309-1314 ◽  
Author(s):  
A. V. Capuco ◽  
E. E. Connor ◽  
D. L. Wood
Keyword(s):  
Mammary Gland ◽  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Thyroid Hormone Receptor ◽  
Physiological State ◽  
Expression Patterns ◽  
Type I ◽  
Hormone Activity ◽  
Iodothyronine Deiodinase ◽  
Copy Numbers

Thyroid hormones are galactopoietic and help to establish the mammary gland’s metabolic priority during lactation. Expression patterns for genes that can alter tissue sensitivity to thyroid hormones and thyroid hormone activity were evaluated in the mammary gland and liver of cows at 53, 35, 20, and 7 days before expected parturition, and 14 and 90 days into the subsequent lactation. Transcript abundance for the three isoforms of iodothyronine deiodinase, type I ( DIO1), type II ( DIO2) and type III ( DIO3), thyroid hormone receptors alpha1 ( TRα 1), alpha2 ( TRα 2) and beta1 ( TRβ 1), and retinoic acid receptors alpha ( RXRα) and gamma ( RXRγ), which act as coregulators of thyroid hormone receptor action, were evaluated by quantitative RT-PCR. The DIO3 is a 5-deiodinase that produces inactive iodothyronine metabolites, whereas DIO1 and DIO2 generate the active thyroid hormone, triiodothyronine, from the relatively inactive precursor, thyroxine. Low copy numbers of DIO3 transcripts were present in mammary gland and liver. DIO2 was the predominant isoform expressed in mammary gland and DIO1 was the predominant isoform expressed in liver. Quantity of DIO1 mRNA in liver tissues did not differ with physiological state, but tended to be lowest during lactation. Quantity of DIO2 mRNA in mammary gland increased during lactation ( P < 0.05), with copy numbers at 90 days of lactation 6-fold greater than at 35 and 20 days prepartum. When ratios of DIO2/DIO3 mRNA were evaluated, the increase was more pronounced (>100-fold). Quantity of TRβ 1 mRNA in mammary gland increased with onset of lactation, whereas TRα 1 and TRα 2 transcripts did not vary with physiological state. Conversely, quantity of RXRα mRNA decreased during late gestation to low levels during early lactation. Data suggest that increased expression of mammary TRβ 1 and DIO2, and decreased RXRα, provide a mechanism to increase thyroid hormone activity within the mammary gland during lactation.

scholarly journals Endoplasmic Reticulum Stress Induces Myostatin High Molecular Weight Aggregates and Impairs Mature Myostatin Secretion

2018 ◽  
Vol 55 (11) ◽  
pp. 8355-8373 ◽  
Author(s):  
Rishibha Sachdev ◽  
Karin Kappes-Horn ◽  
Lydia Paulsen ◽  
Yvonne Duernberger ◽  
Catharina Pleschka ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
High Molecular Weight

scholarly journals Coupled Translocation Events Generate Topological Heterogeneity at the Endoplasmic Reticulum Membrane

1998 ◽  
Vol 9 (9) ◽  
pp. 2681-2697 ◽  
Author(s):  
Kenneth Moss ◽  
Andrew Helm ◽  
Yun Lu ◽  
Alvina Bragin ◽  
William R. Skach
Keyword(s):  
Endoplasmic Reticulum ◽  
Structural Features ◽  
Endoplasmic Reticulum Membrane ◽  
Type I ◽  
Type Ii ◽  
Hydrophobic Residues ◽  
P Glycoprotein ◽  
C Terminus ◽  
Signal Anchor ◽  
Hydrophilic Residues

Topogenic determinants that direct protein topology at the endoplasmic reticulum membrane usually function with high fidelity to establish a uniform topological orientation for any given polypeptide. Here we show, however, that through the coupling of sequential translocation events, native topogenic determinants are capable of generating two alternate transmembrane structures at the endoplasmic reticulum membrane. Using defined chimeric and epitope-tagged full-length proteins, we found that topogenic activities of two C-trans (type II) signal anchor sequences, encoded within the seventh and eighth transmembrane (TM) segments of human P-glycoprotein were directly coupled by an inefficient stop transfer (ST) sequence (TM7b) contained within the C-terminus half of TM7. Remarkably, these activities enabled TM7 to achieve both a single- and a double-spanning TM topology with nearly equal efficiency. In addition, ST and C-trans signal anchor activities encoded by TM8 were tightly linked to the weak ST activity, and hence topological fate, of TM7b. This interaction enabled TM8 to span the membrane in either a type I or a type II orientation. Pleiotropic structural features contributing to this unusual topogenic behavior included 1) a short, flexible peptide loop connecting TM7a and TM7b, 2) hydrophobic residues within TM7b, and 3) hydrophilic residues between TM7b and TM8.

scholarly journals The catalytic activity of the endoplasmic reticulum-resident protein microsomal epoxide hydrolase towards carcinogens is retained on inversion of its membrane topology

1996 ◽  
Vol 319 (1) ◽  
pp. 131-136 ◽  
Author(s):  
Thomas FRIEDBERG ◽  
Romy HOLLER ◽  
Bettina LÖLLMANN ◽  
Michael ARAND ◽  
Franz OESCH
Keyword(s):  
Endoplasmic Reticulum ◽  
Catalytic Activity ◽  
Epoxide Hydrolase ◽  
Membrane Topology ◽  
Microsomal Epoxide Hydrolase ◽  
Type I ◽  
Type Ii ◽  
Membrane Orientation ◽  
N Terminus ◽  
Cytochrome P 450

Diol epoxides formed by the sequential action of cytochrome P-450 and the microsomal epoxide hydrolase (mEH) in the endoplasmic reticulum (ER) represent an important class of ultimate carcinogenic metabolites of polycyclic aromatic hydrocarbons. The role of the membrane orientation of cytochrome P-450 and mEH relative to each other in this catalytic cascade is not known. Cytochrome P-450 is known to have a type I topology. According to the algorithm of Hartman, Rapoport and Lodish [(1989) Proc. Natl. Acad. Sci. U.S.A. 86, 5786–5790], which allows the prediction of the membrane topology of proteins, mEH should adopt a type II membrane topology. Experimentally, mEH membrane topology has been disputed. Here we demonstrate that, in contrast with the theoretical prediction, the rat mEH has exclusively a type I membrane topology. Moreover we show that this topology can be inverted without affecting the catalytic activity of mEH. Our conclusions are supported by the observation that two mEH constructs (mEHg1 and mEHg2), containing engineered potential glycosylation sites at two separate locations after the C-terminal site of the membrane anchor, were not glycosylated in fibroblasts. However, changing the net charge at the N-terminus of these engineered mEH proteins by +3 resulted in proteins (++mEHg1 and ++mEHg2) that became glycosylated and consequently had a type II topology. The sensitivity of these glycosylated proteins to endoglycosidase H indicated that, like the native mEH, they are still retained in the ER. The engineered mEH proteins were integrated into membranes as they were resistant to alkaline extraction. Interestingly, an insect mEH with a charge distribution in its N-terminus similar to ++mEHg1 has recently been isolated. This enzyme might well display a type II topology instead of the type I topology of the rat mEH. Importantly, mEHg1, having the natural cytosolic orientation, as well as ++mEHg1, having an artificial luminal orientation, displayed rather similar substrate turnovers for the mutagenic metabolite benzo[a]pyrene 4,5-oxide. To our knowledge this is the first report demonstrating that topological inversion of a protein within the membrane of the ER has only a moderate effect on its enzymic activity, despite differences in folding pathways and redox environments on each side of the membrane. This observation represents an important step in the evaluation of the influence of mEH membrane orientation in the cascade of events leading to the formation of ultimate carcinogenic metabolites, and for studying the general importance of metabolic channelling on the surface of membranes.

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