Resistance to endoplasmic reticulum stress is an acquired cellular characteristic of rheumatoid synovial cells

Yamasaki, Satoshi; Yagishita, Naoko; Tsuchimochi, Kaneyuki; Kato, Y.; Sasaki, Takeshi; Amano, Tetsuya; Beppu, Masatoshi; Aoki, Haruhito; Nakamura, Hiroshi; Nishioka, Kusuki; Nakajima, Takeshi

doi:10.3892/ijmm.18.1.113

Cited by 13 publications

(19 citation statements)

References 14 publications

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“…Sustained and severe ER stress may lead to cell death, while mild to moderate ER stress may initiate an adaptive survival response called unfolded protein responses (UPR) to alleviate the life threatening of ER stress. It has been proved that human somatic cells can acquire the ability to become tolerant to ER stress by the adaptive mechanism [19]. Here we show that human lung caner cells can become tolerant to ER stress by stepwise exposure to increasing concentrations of TM, and these ERST lung cancer cells can acquire high ability to resist CDDP-induced cell growth inhibition and apoptosis (Fig.…”

Section: Discussionmentioning

confidence: 87%

Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells

Yu¹,

Wang²,

Liu³

et al. 2011

Lung Cancer

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Section: Discussionmentioning

confidence: 87%

Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells

Yu¹,

Wang²,

Liu³

et al. 2011

Lung Cancer

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“…Elevated RNF5 expression is also reported in breast cancer and other tumor types and is associated with cytoskeletal organization, proliferation, and resistance to chemotherapy (28). Conversely, excessive degradation (hyper-ERAD) may result in severe pathological consequences, including rheumatoid arthritis, as was demonstrated for Hrd1 ligase (synviolin) (29,30). That a tissuespecific effect may render RNF5 more important in targeting ubiquitination-dependent degradation of select misfolded proteins cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Endoplasmic Reticulum-associated Degradation by RNF5-dependent Ubiquitination of JNK-associated Membrane Protein (JAMP)

Tcherpakov

Delaunay

Toth

et al. 2009

Journal of Biological Chemistry

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Clearance of misfolded proteins by endoplasmic reticulum (ER)-associated degradation (ERAD) requires concerted activity of chaperones, adaptor proteins, ubiquitin ligases, and proteasomes. RNF5 is a ubiquitin ligase anchored to the ER membrane implicated in ERAD via ubiquitination of misfolded proteins. Among RNF5-associated proteins is JNK-associated membrane protein (JAMP), a 7-transmembrane protein located within the ER membrane that facilitates degradation of misfolded proteins through recruitment of proteasomes and ERAD regulatory components. Here we demonstrate that RNF5 associates with JAMP in the ER membrane. This association results in Ubc13-dependent RNF5-mediated noncanonical ubiquitination of JAMP. This ubiquitination does not alter JAMP stability but rather inhibits its association with Rpt5 and p97. Consequently, clearance of misfolded proteins, such as CFTR⌬508 and T cell receptor ␣, is less efficient, resulting in their greater accumulation. Significantly, the RNF5 effect on JAMP is seen prior to and after ER stress response, thereby highlighting a novel mechanism to limit ERAD and proteasome assembly at the ER, to the actual ER stress response.Degradation of misfolded proteins is part of a complex quality control system that clears diverse proteins independent of sequence or functional similarity (1-3). The unfolded protein response reduces the burden caused by unfolded protein accumulation in the endoplasmic reticulum (ER) 2 (4), in part by activating its key regulatory proteins IRE1-XBP1 and ATF6, which results in transcriptional activation of genes important for unfolded protein response, including components of the ER-associated degradation system (ERAD) (5).ERAD is regulated by an ER quality control system that marks proteins that cannot fold or assemble into multiprotein complexes for ubiquitin-dependent degradation (1-3). This system consists of molecular chaperones such as BiP (1-3), which interacts with misfolded protein to enable their transfer across the ER membrane via the multispanning membrane proteins Derlin-1/2/3 and Sec61(6), and the AAA (ATPase p97 (also known as VCP or cdc48)). Subsequent to translocation, misfolded proteins are ubiquitinated via ERanchored ubiquitin ligases, such as the vertebrate gp78, Parkin, RNF5/RMA1, and Hrd1 (7-10), followed by proteasome-mediated degradation.RNF5 (RING finger domain E3 ligase; also known as RMA1) is one of the few ER-associated E3 ubiquitin ligases. Anchored to the ER membrane via its C terminus, RNF5 consists of a classic RING domain (which confers ligase activity), a single transmembrane-spanning domain located within the C-terminal region, and a formin-like homology domain. RNF5 has been shown to promote degradation of misfolded proteins, such as mutant CFTR (CFTR⌬508) (9, 10). Intriguingly, RNF5-mediated degradation of mutant CFTR requires cooperation with another ligase, as has also been shown for gp78 or CHIP, suggesting a two-stage process in which the first ligase promotes substrate mono-ubiquitination, whereas the second media...

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“…Proteomic analysis of normal and OA chondrocytes has revealed changes in stress-related proteins (Ruiz-Romero et al 2008). Yamasaki et al (2006) reported resistance to ER stress-induced apoptosis in rheumatoid arthritic synovial cells. Additionally, ER stress is implicated in skeletal dysplasias such as pseudoachondroplasia and multiple epiphyseal dysplasia, in which mutated cartilage oligomeric matrix protein and collagen type IX are retained within the ER (Hecht et al 1998).…”

Section: Discussionmentioning

confidence: 99%

Advanced Osteoarthritis in Humans Is Associated With Altered Collagen VI Expression and Upregulation of ER-stress Markers Grp78 and Bag-1

Nugent

Speicher

Gradisar

et al. 2009

J Histochem Cytochem.

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; and Summa Health Systems, Akron, Ohio (IG) S U M M A R Y To test the hypothesis that a perturbation of endoplasmic reticulum (ER) function is involved in the pathogenesis of osteoarthritis (OA), articular cartilage was isolated from non-OA patients secondary to resection of osteo-or chondrosarcomas. Intra-joint samples of minimal and advanced osteoarthritic cartilage were isolated from patients undergoing total knee arthroplasty and scored for disease severity. Glucose-regulated protein-78 (grp78) and bcl-2-associated athanogene-1 (bag-1) were detected via immunofluorescence as markers of non-homeostatic ER function. Additionally, the expression of type VI collagen and its integrin receptor, NG2, was determined to examine cartilage matrix health and turnover. There was an upregulation of grp78 in advanced OA, and variable expression in minimal OA. Non-OA cartilage was consistently grp78 negative. The downstream regulator bag-1 was also upregulated in OA compared with normal cartilage. Collagen VI was mainly cellassociated in non-OA cartilage, with a more widespread distribution observed in OA cartilage along with increased intracellular staining intensity. The collagen VI integral membrane proteoglycan receptor NG2 was downregulated in advanced OA compared with its patientmatched minimally involved cartilage sample. These results suggest that chondrocytes exhibit ER stress during OA, in association with upregulation of a large secreted molecule, type VI collagen. (J Histochem Cytochem 57:923-931, 2009) K E Y W O R D S osteoarthritis cartilage ER stress bag-1 grp78 collagen VI NG2 OSTEOARTHRITIS (OA) IS A PROGRESSIVE DISEASE, with changes in chondrocyte gene expression and extracellular matrix (ECM) composition occurring before macroscopic structural damage is observed (Hamerman 1989). Articular chondrocytes in OA exhibit a hypermetabolic phenotype, with studies describing highly proliferative clonal chondrocytes, along with the upand downregulation of ECM molecules such as aggrecan

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Resistance to endoplasmic reticulum stress is an acquired cellular characteristic of rheumatoid synovial cells

Cited by 13 publications

References 14 publications

Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells

Akt is the downstream target of GRP78 in mediating cisplatin resistance in ER stress-tolerant human lung cancer cells

Regulation of Endoplasmic Reticulum-associated Degradation by RNF5-dependent Ubiquitination of JNK-associated Membrane Protein (JAMP)

Advanced Osteoarthritis in Humans Is Associated With Altered Collagen VI Expression and Upregulation of ER-stress Markers Grp78 and Bag-1

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