Endoplasmic reticulum quality control by garbage disposal

Kadowaki, Hisae; Nishitoh, Hideki

doi:10.1111/febs.14589

Cited by 26 publications

(22 citation statements)

References 81 publications

(98 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Alternatively, autophagy and apoptosis work together and cell dies for both mechanisms (Figure 1C). The subcellular compartments where autophagy and apoptosis could be interconnected are the endoplasmic reticulum [16], mitochondria [17] and lysosomes [18].…”

Section: Cross-talk Between Autophagic Apoptotic and Necrotic Patmentioning

confidence: 99%

Targeting Autophagy to Overcome Human Diseases

Condello

Pellegrini

Caraglia

et al. 2019

IJMS

100

View full text Add to dashboard Cite

Autophagy is an evolutionarily conserved cellular process, through which damaged organelles and superfluous proteins are degraded, for maintaining the correct cellular balance during stress insult. It involves formation of double-membrane vesicles, named autophagosomes, that capture cytosolic cargo and deliver it to lysosomes, where the breakdown products are recycled back to cytoplasm. On the basis of degraded cell components, some selective types of autophagy can be identified (mitophagy, ribophagy, reticulophagy, lysophagy, pexophagy, lipophagy, and glycophagy). Dysregulation of autophagy can induce various disease manifestations, such as inflammation, aging, metabolic diseases, neurodegenerative disorders and cancer. The understanding of the molecular mechanism that regulates the different phases of the autophagic process and the role in the development of diseases are only in an early stage. There are still questions that must be answered concerning the functions of the autophagy-related proteins. In this review, we describe the principal cellular and molecular autophagic functions, selective types of autophagy and the main in vitro methods to detect the role of autophagy in the cellular physiology. We also summarize the importance of the autophagic behavior in some diseases to provide a novel insight for target therapies.

show abstract

Section: Cross-talk Between Autophagic Apoptotic and Necrotic Patmentioning

confidence: 99%

Targeting Autophagy to Overcome Human Diseases

Condello

Pellegrini

Caraglia

et al. 2019

IJMS

100

View full text Add to dashboard Cite

show abstract

“…Autophagy and proteasomal degradation were examined because they are the cellular mechanisms responsible for removing misfolded protein from the ER. ( 30 ) Previously, we showed that mutant‐COMP accumulation in the ER of murine MT‐COMP growth plate chondrocytes occurs because autophagy was blocked by elevated mTORC1 signaling. ( 4 ) It remains unclear whether proteasome degradation plays a role in this ER‐stress‐induced chondrocyte pathology because the COMP‐ECM matrix within the ER may prohibit translocation from the ER to the proteasome.…”

Section: Resultsmentioning

confidence: 99%

“…Autophagy and proteasomal degradation were examined as they are the cellular mechanisms responsible for removing misfolded protein from the ER (30) . Previously, we showed that MT-COMP accumulation in the ER of murine MT-COMP growth plate chondrocytes occurs because autophagy was blocked by elevated mTORC1 signaling (4) .…”

Section: Resveratrol Treatment Reactivates Autophagy In Mt-comp Chondmentioning

confidence: 99%

Resveratrol Reduces COMPopathy in Mice Through Activation of Autophagy

et al. 2021

View full text Add to dashboard Cite

Misfolding mutations in cartilage oligomeric matrix protein (COMP) cause it to be retained within the endoplasmic reticulum (ER) of chondrocytes, stimulating a multitude of damaging cellular responses including ER stress, inflammation, and oxidative stress, which ultimately culminates in the death of growth plate chondrocytes and pseudoachondroplasia (PSACH). Previously, we demonstrated that an antioxidant, resveratrol, substantially reduces the intracellular accumulation of mutant-COMP, dampens cellular stress, and lowers the level of growth plate chondrocyte death. In addition, we showed that resveratrol reduces mammalian target of rapamycin complex 1 (mTORC1) signaling, suggesting a potential mechanism. In this work, we investigate the role of autophagy in treatment of COMPopathies. In cultured chondrocytes expressing wild-type COMP or mutant-COMP, resveratrol significantly increased the number of Microtubule-associated protein 1A/1B-light chain 3 (LC3) vesicles, directly demonstrating that resveratrol-stimulated autophagy is an important component of the resveratrol-driven mechanism responsible for the degradation of mutant-COMP. Moreover, pharmacological inhibitors of autophagy suppressed degradation of mutant-COMP in our established mouse model of PSACH. In contrast, blockage of the proteasome did not substantially alter resveratrol clearance of mutant-COMP from growth plate chondrocytes. Mechanistically, resveratrol increased SIRT1 and PP2A expression and reduced MID1 expression and activation of phosphorylated protein kinase B (pAKT) and mTORC1 signaling in growth plate chondrocytes, allowing clearance of mutant-COMP by autophagy. Importantly, we show that optimal reduction in growth plate pathology, including decreased mutant-COMP retention, decreased mTORC1 signaling, and restoration of chondrocyte proliferation was attained when treatment was initiated between birth to 1 week of age in MT-COMP mice, translating to birth to approximately 2 years of age in children with PSACH. These results clearly demonstrate that resveratrol stimulates clearance of mutant-COMP by an autophagy-centric mechanism.

show abstract

“…Autophagy and proteasomal degradation were examined as they are the cellular mechanisms responsible for removing misfolded protein from the ER (33) . Previously, we showed that MT-COMP accumulation in the ER of murine MT-COMP growth plate chondrocytes occurs because autophagy was blocked by elevated mTORC1 signaling (4) .…”

Section: Resveratrol Treatment Reactivates Autophagy In Mt-comp Chondmentioning

confidence: 99%

Resveratrol reduces COMPopathy in mice through activation of autophagy

Hecht

Coustry

Veerisetty

et al. 2020

Preprint

View full text Add to dashboard Cite

Misfolding mutations in cartilage oligomeric matrix protein (COMP) cause it to be retained within in ER of chondrocytes, stimulating a multitude of damaging cellular responses including ER stress, inflammation and oxidative stress which ultimately culminates in the death of growth plate chondrocytes and pseudoachondroplasia (PSACH). Previously, we demonstrated that an antioxidant, resveratrol, substantially reduces the intracellular accumulation of mutant COMP, dampens cellular stress and lowers the level of growth plate chondrocyte death. In addition, we showed that resveratrol reduces mTORC1 (mammalian target of rapamycin complex 1) signaling, suggesting a potential mechanism. In this work, we investigate the role of autophagy in treatment of COMPopathies. In cultured chondrocytes expressing wild type or mutant COMP (MT-COMP), resveratrol significantly increased the number of large LC3 vesicles, directly demonstrating that resveratrol stimulated autophagy is an important component of the resveratrol-driven mechanism responsible for the degradation of mutant COMP. Moreover, pharmacological inhibitors of autophagy suppressed degradation of MT-COMP in our established mouse model of PSACH. In contrast, blockage of the proteasome did not substantially alter resveratrol clearance of mutant COMP from growth plate chondrocytes. Mechanistically, resveratrol increased SIRT1 and PP2A expression and reduced MID1 expression and activation of pAKT and mTORC1 signaling in growth plate chondrocytes, allowing clearance of mutant COMP by autophagy. Importantly, we show that optimal reduction in growth plate pathology, including decreased mutant COMP retention, decreased mTORC1 signaling and restoration of chondrocyte proliferation was attained when treatment was initiated between birth to one week of age in MT-COMP mice, translating to birth to approximately 2 years of age in PSACH children. These results clearly demonstrate that resveratrol stimulates clearance of mutant COMP by an autophagy-centric mechanism. Key Words: pseudoachondroplasia, autophagy, resveratrol, dwarfism, cartilage oligomeric matrix protein (COMP), proteasome, mTORC1

show abstract

Endoplasmic reticulum quality control by garbage disposal

Cited by 26 publications

References 81 publications

Targeting Autophagy to Overcome Human Diseases

Targeting Autophagy to Overcome Human Diseases

Resveratrol Reduces COMPopathy in Mice Through Activation of Autophagy

Resveratrol reduces COMPopathy in mice through activation of autophagy

Contact Info

Product

Resources

About