PERK-mediated translational control is required for collagen secretion in chondrocytes

Hisanaga, Satoshi; Miyake, Masato; Taniuchi, Shusuke; Oyadomari, Miho; Morimoto, Masatoshi; Sato, Ryosuke; Hirose, Jun; Mizuta, Hiroshi; Oyadomari, Seiichi

doi:10.1038/s41598-017-19052-9

Cited by 17 publications

(14 citation statements)

References 53 publications

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“…Misfolded or aggregated proteins are prone to forming stable, detergent-insoluble, high molecular weight (HMW) oligomers together with molecular chaperones (Johnston et al, 1998). We previously developed and modified a method to estimate the amount of misfolded or aggregated protein in the ER based on the levels of the molecular chaperone BiP (also known as HSPA5) in SDS-resistant HMW complexes ( AGGREGATED ) (Marciniak et al, 2004; Hisanaga et al, 2018) (Figure 5D). Compared with the levels of BiP in the INPUT fraction, the levels of BiP in the AGGREGATED fraction corresponding to misfolded or aggregated proteins in the ER were increased by Tm treatment (3.1-fold of UT), and this increase was significantly suppressed by IBT21 treatment (1.7-fold of UT) (Figure 5E and F).…”

Section: Resultsmentioning

confidence: 99%

Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity

Kitakaze

Taniuchi

Kawano

et al. 2019

eLife

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The endoplasmic reticulum (ER) is responsible for folding secretory and membrane proteins, but disturbed ER proteostasis may lead to protein aggregation and subsequent cellular and clinical pathologies. Chemical chaperones have recently emerged as a potential therapeutic approach for ER stress-related diseases. Here, we identified 2-phenylimidazo[2,1-b]benzothiazole derivatives (IBTs) as chemical chaperones in a cell-based high-throughput screen. Biochemical and chemical biology approaches revealed that IBT21 directly binds to unfolded or misfolded proteins and inhibits protein aggregation. Finally, IBT21 prevented cell death caused by chemically induced ER stress and by a proteotoxin, an aggression-prone prion protein. Taken together, our data show the promise of IBTs as potent chemical chaperones that can ameliorate diseases resulting from protein aggregation under ER stress.

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Section: Resultsmentioning

confidence: 99%

Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity

Kitakaze

Taniuchi

Kawano

et al. 2019

eLife

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“…The intracellular retention of FT TTR A25T observed upon co-pretreatment with Tg and ISRIB likely reflects increased accumulation of non-native TTR conformations within the ER, as observed for other proteins 28,29,31 . To test this, we measured the intracellular interaction between FT TTR A25T and ER chaperones (which bind non-native protein conformations) in HEK293T cells pretreated with Tg and/or ISRIB for 16 h using an established immunopurification (IP)/immunoblotting (IB) assay 38 .…”

Section: Resultsmentioning

confidence: 85%

“…In addition, PERK regulates both ER-to-Golgi anterograde trafficking and ER-associated degradation 25,26 , the latter a primary mechanism by which cells degrade ER proteins 27 . As such, genetic or pharmacologic inhibition of PERK signaling disrupts secretory proteostasis to reduce the secretion and increase the intracellular accumulation of proteins such as collagen, insulin, or mutant rhodopsin as high molecular weight (HMW) aggregates 28–31 . These results define an important role for PERK in regulating ER proteostasis in response to pathologic insults.…”

Section: Introductionmentioning

confidence: 99%

PERK Signaling Regulates Extracellular Proteostasis of an Amyloidogenic Protein During Endoplasmic Reticulum Stress

Romine

Wiseman

2019

Sci Rep

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The PERK arm of the unfolded protein response (UPR) regulates cellular proteostasis and survival in response to endoplasmic reticulum (ER) stress. However, the impact of PERK signaling on extracellular proteostasis is poorly understood. We define how PERK signaling influences extracellular proteostasis during ER stress using a conformational reporter of the secreted amyloidogenic protein transthyretin (TTR). We show that inhibiting PERK signaling impairs secretion of destabilized TTR during thapsigargin (Tg)-induced ER stress by increasing its ER retention in chaperone-bound complexes. Interestingly, PERK inhibition increases the ER stress-dependent secretion of TTR in non-native conformations that accumulate extracellularly as soluble oligomers. Pharmacologic or genetic TTR stabilization partially restores secretion of native TTR tetramers. However, PERK inhibition still increases the ER stress-dependent secretion of TTR in non-native conformations under these conditions, indicating that the conformation of stable secreted proteins can also be affected by inhibiting PERK. Our results define a role for PERK in regulating extracellular proteostasis during ER stress and indicate that genetic or aging-related alterations in PERK signaling can exacerbate ER stress-related imbalances in extracellular proteostasis implicated in diverse diseases.

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“…To build and maintain cartilage, a proper function of the endoplasmic reticulum (ER) is essential in chondrocytes, as they are responsible for the production of large amounts of ECM proteins during skeletal development and growth. Due to avascularity of cartilage, the secretory chondrocytes experience a variety of stresses, such as low oxygen tension and limited nutrient conditions [9, 10], and consequently, the protein folding capacity in the cells has to be balanced with physiological parameters like energy and oxygen levels [11]. However, different cellular conditions, e.g., phases of high protein demand or pathologic situations, prevent ER homeostasis and lead to the accumulation of poorly folded proteins.…”

Section: A Proper Er Function Is a Prerequisite For Effective Protmentioning

confidence: 99%

Different Forms of ER Stress in Chondrocytes Result in Short Stature Disorders and Degenerative Cartilage Diseases: New Insights by Cartilage‐Specific ERp57 Knockout Mice

Rellmann¹,

Dreier²

2018

Oxidative Medicine and Cellular Longevity

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Cartilage is essential for skeletal development by endochondral ossification. The only cell type within the tissue, the chondrocyte, is responsible for the production of macromolecules for the extracellular matrix (ECM). Before proteins and proteoglycans are secreted, they undergo posttranslational modification and folding in the endoplasmic reticulum (ER). However, the ER folding capacity in the chondrocytes has to be balanced with physiological parameters like energy and oxygen levels. Specific cellular conditions, e.g., a high protein demand, or pathologic situations disrupt ER homeostasis and lead to the accumulation of poorly folded or misfolded proteins. This state is called ER stress and induces a cellular quality control system, the unfolded protein response (UPR), to restore homeostasis. Different mouse models with ER stress in chondrocytes display comparable skeletal phenotypes representing chondrodysplasias. Therefore, ER stress itself seems to be involved in the pathogenesis of these diseases. It is remarkable that chondrodysplasias with a comparable phenotype arise independent from the sources of ER stress, which are as follows: (1) mutations in ECM proteins leading to aggregation, (2) deficiencies in ER chaperones, (3) mutations in UPR signaling factors, or (4) deficiencies in the degradation of aggregated proteins. In any case, the resulting UPR substantially impairs ECM protein synthesis, chondrocyte proliferation, and/or differentiation or regulation of autophagy and apoptosis. Notably, chondrodysplasias arise no matter if single or multiple events are affected. We analyzed cartilage-specific ERp57 knockout mice and demonstrated that the deficiency of this single protein disulfide isomerase, which is responsible for formation of disulfide bridges in ECM glycoproteins, is sufficient to induce ER stress and to cause an ER stress-related bone phenotype. These mice therefore qualify as a novel model for the analysis of ER stress in chondrocytes. They give new insights in ER stress-related short stature disorders and enable the analysis of ER stress in other cartilage diseases, such as osteoarthritis.

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PERK-mediated translational control is required for collagen secretion in chondrocytes

Cited by 17 publications

References 53 publications

Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity

Cell-based HTS identifies a chemical chaperone for preventing ER protein aggregation and proteotoxicity

PERK Signaling Regulates Extracellular Proteostasis of an Amyloidogenic Protein During Endoplasmic Reticulum Stress

Different Forms of ER Stress in Chondrocytes Result in Short Stature Disorders and Degenerative Cartilage Diseases: New Insights by Cartilage‐Specific ERp57 Knockout Mice

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