ERp57 is essential for efficient folding of glycoproteins sharing common structural domains

Jessop, Catherine E.; Chakravarthi, Seema; Garbi, Natalio; Hämmerling, Günter J.; Lovell, Simon C.; Bulleid, Neil J.

doi:10.1038/sj.emboj.7601505

Cited by 185 publications

(210 citation statements)

References 37 publications

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“…We have shown here that a proper function of ERp57 in chondrocytes, most likely as a chaperone with PDI activity, (18,22) is essential for normal postnatal growth. This especially applies to males at the age of 1 month, around the pubertal growth spurt, when large quantities of new ECM proteins are synthesized, folded, and secreted.…”

Section: Discussionmentioning

confidence: 76%

“…Among these substrates different ECM proteins, such as collagen IV, laminins, and agrin, or ECM receptors like integrins are included. (22) Perturbation of the chaperone function, such as inhibition of disulfide bond formation, can result in the accumulation of unfolded or misfolded proteins in the ER, which leads to ER stress. In eukaryotic cells ER stress can be reversed by the unfolded protein response (UPR), an adaptive mechanism that aims to clear unfolded proteins and restore ER homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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ER Stress During the Pubertal Growth Spurt Results in Impaired Long-Bone Growth in Chondrocyte-Specific ERp57 Knockout Mice

Linz

Knieper

Gronau

et al. 2015

Journal of Bone and Mineral Research

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Long-bone growth by endochondral ossification is cooperatively accomplished by chondrocyte proliferation, hypertrophic differentiation, and appropriate secretion of collagens, glycoproteins, and proteoglycans into the extracellular matrix (ECM). Before folding and entering the secretory pathway, ECM macromolecules in general are subject to extensive posttranslational modification, orchestrated by chaperone complexes in the endoplasmic reticulum (ER). ERp57 is a member of the protein disulfide isomerase (PDI) family and facilitates correct folding of newly synthesized glycoproteins by rearrangement of native disulfide bonds. Here, we show that ERp57-dependent PDI activity is essential for postnatal skeletal growth, especially during the pubertal growth spurt characterized by intensive matrix deposition. Loss of ERp57 in growth plates of cartilage-specific ERp57 knockout mice (ERp57 KO) results in ER stress, unfolded protein response (UPR), reduced proliferation, and accelerated apoptotic cell death of chondrocytes. Together this results in a delay of long-bone growth with the following characteristics: (1) enlarged growth plates; (2) expanded hypertrophic zones; (3) retarded osteoclast recruitment; (4) delayed remodeling of the proteoglycan-rich matrix; and (5) reduced numbers of bone trabeculae. All the growth plate and bone abnormalities, however, become attenuated after the pubertal growth spurt, when protein synthesis is decelerated and, hence, ERp57 function is less essential.

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

ER Stress During the Pubertal Growth Spurt Results in Impaired Long-Bone Growth in Chondrocyte-Specific ERp57 Knockout Mice

Linz

Knieper

Gronau

et al. 2015

Journal of Bone and Mineral Research

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“…Nevertheless, Rot1 is an essential protein, and we believe that Rot1 plays a unique role(s) in protein folding in the ER. To illustrate Rot1-dependent protein folding in vivo more comprehensively, large-scale identification and examination of the substrate proteins using a proteomic approach such that of Kerner et al (2005) and Jessop et al (2007) would be desirable.…”

Section: Discussionmentioning

confidence: 99%

Saccharomyces cerevisiaeRot1 Is an Essential Molecular Chaperone in the Endoplasmic Reticulum

Takeuchi

Kohno

2008

MBoC

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Molecular chaperones prevent aggregation of denatured proteins in vitro and are thought to support folding of diverse proteins in vivo. Chaperones may have some selectivity for their substrate proteins, but knowledge of particular in vivo substrates is still poor. We here show that yeast Rot1, an essential, type-I ER membrane protein functions as a chaperone. Recombinant Rot1 exhibited antiaggregation activity in vitro, which was partly impaired by a temperature-sensitive rot1-2 mutation. In vivo, the rot1-2 mutation caused accelerated degradation of five proteins in the secretory pathway via ER-associated degradation, resulting in a decrease in their cellular levels. Furthermore, we demonstrate a physical and probably transient interaction of Rot1 with four of these proteins. Collectively, these results indicate that Rot1 functions as a chaperone in vivo supporting the folding of those proteins. Their folding also requires BiP, and one of these proteins was simultaneously associated with both Rot1 and BiP, suggesting that they can cooperate to facilitate protein folding. The Rot1-dependent proteins include a soluble, type I and II, and polytopic membrane proteins, and they do not share structural similarities. In addition, their dependency on Rot1 appeared different. We therefore propose that Rot1 is a general chaperone with some substrate specificity.

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“…We did immunoprecipitation experiments with anti-TUBB3 antibody using total lysates and mitochondrial extracts from A2780, TC1, and OVCAR-3 cells. To identify proteins forming mixed disulfide bonds with TUBB3, eluted proteins from immunoprecipitation were subjected to two-dimensional nonreduced/reduced SDS-PAGE analysis with first dimension carried out under nonreducing conditions to separate mixed disulfide complexes and the second dimension run on reducing conditions to resolve the mixed disulfides according to their individual size (25).…”

Section: Tubb3 Is Glycosylated and Phosphorylatedmentioning

confidence: 99%

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

Cicchillitti¹,

Penci²,

Michele

et al. 2008

Molecular Cancer Therapeutics

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Class III B-tubulin (TUBB3) has been discovered as a marker of drug resistance in human cancer. To get insights into the mechanisms by which this protein is involved in drug resistance, we analyzed TUBB3 in a panel of drug-sensitive and drug-resistant cell lines. We identified two main different isoforms of TUBB3 having a specific electrophoretic profile. We showed that the apparently higher molecular weight isoform is glycosylated and phosphorylated and it is localized in the cytoskeleton. The apparently lower molecular weight isoform is instead found exclusively in mitochondria. We observed that levels of phosphorylation and glycosylation of TUBB3 are associated with the resistant phenotype and compartmentalization into cytoskeleton. By two-dimensional nonreduced/reduced SDS-PAGE analysis, we also found that TUBB3 protein in vivo forms protein complexes through intermolecular disulfide bridges. Through TUBB3 immunoprecipitation, we isolated protein species able to interact with TUBB3. Following trypsin digestion, these proteins were characterized by mass spectrometry analysis. Functional analysis revealed that these proteins are involved in adaptation to oxidative stress and glucose deprivation, thereby suggesting that TUBB3 is a survival factor able to directly contribute to drug resistance. Moreover, glycosylation of TUBB3 could represent an attractive pathway whose inhibition could hamper cytoskeletal compartmentalization and TUBB3 function.

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ERp57 is essential for efficient folding of glycoproteins sharing common structural domains

Cited by 185 publications

References 37 publications

ER Stress During the Pubertal Growth Spurt Results in Impaired Long-Bone Growth in Chondrocyte-Specific ERp57 Knockout Mice

ER Stress During the Pubertal Growth Spurt Results in Impaired Long-Bone Growth in Chondrocyte-Specific ERp57 Knockout Mice

Saccharomyces cerevisiaeRot1 Is an Essential Molecular Chaperone in the Endoplasmic Reticulum

Proteomic characterization of cytoskeletal and mitochondrial class III β-tubulin

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