mTORC1 senses stresses: Coupling stress to proteostasis

Su, Kuo‐Hui; Dai, Chengkai

doi:10.1002/bies.201600268

Cited by 69 publications

(50 citation statements)

References 135 publications

(186 reference statements)

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“…The above results led us to hypothesize that the vulnerability of HGSOC cells to reduced proteasome activity, maybe, at least in part due to proteotoxic stress. Inhibition of proteasomal degradation of proteins induces proteotoxicity leading to activation of terminal UPR and attenuates protein translation [51,54,55]. Consistent with this hypothesis, polyubiquitinated proteins accumulated following UCHL1 silencing and treatment with UCHL1 inhibitor, LDN57444 in HGSOC cells, Kuramochi, and OVCAR4 ( Figures 6A and 6B).…”

Section: Uchl1 Inhibition Induces Terminal Stress Response and Attenusupporting

confidence: 68%

Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

Tangri

Lighty

Loganathan

et al. 2020

Preprint

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High-grade serous ovarian cancer (HGSOC) is characterized by genomic instability, DNA damage, oxidative stress, and high metabolic demand that contribute to misfolded proteins and proteotoxicity. However, the underlying mechanisms that maintain protein homeostasis to promote HGSOC growth remain poorly understood. In this study, we report that the neuronal deubiquitinating enzyme, UCHL1 (ubiquitin C-terminal hydrolase L1) is overexpressed in HGSOC and regulates protein homeostasis. UCHL1 expression was markedly increased in HGSOC patient tumors and serous tubal intraepithelial carcinoma (HGSOC precursor lesions) and correlated with higher tumor grade and poor patient survival. UCHL1 inhibition reduced proliferation and invasion of HGSOC cells as well as significantly reduced the in vivo metastatic growth of the ovarian cancer xenografts. Transcriptional profiling of UCHL1 silenced HGSOC cells revealed down-regulation of genes implicated with proteasome activity along with the upregulation of endoplasmic reticulum (ER) stress-mediated genes. Silencing UCHL1 resulted in reduced expression of proteasome subunit alpha 7 (PSMA7) and acylaminoacyl peptide hydrolase (APEH) leading to a decrease in proteasome activity, accumulation of polyubiquitinated proteins, and reduced mTORC1 activity and protein synthesis. This induced ER-stress mediated pro-apoptotic factors, including ATF3 (activating transcription factor 3). In addition, the growth of HGSOC cells was significantly reduced upon silencing PSMA7 and APEH or inhibiting proteasome activity. Together, these results indicate that the UCHL1-PSMA7-APEH axis mediates the degradation of misfolded proteins, salvage amino acids for protein synthesis, and maintain protein homeostasis. This study highlights protein homeostasis as a therapeutic vulnerability in HGSOC and identifies UCHL1 and APEH inhibitors as novel therapeutic strategies.

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Section: Uchl1 Inhibition Induces Terminal Stress Response and Attenusupporting

confidence: 68%

Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

Tangri

Lighty

Loganathan

et al. 2020

Preprint

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“…The interaction of the serine-threonine kinase mTORC1 with autophagy is mediated by the mTOR-ULK1/2 signaling pathway ( Figure 1) [67][68][69]. mTORC1 senses and responds to diverse stress conditions, including metabolic/energetic stresses, oxidative stress, ER stress, and genotoxic stress, and it is inactivated by most if not all of these stresses [70,71]. Suppression of mTORC1 activates autophagy, and therefore, mTORC1 is considered a negative regulator of autophagy.…”

Section: Mtorc1-ulk1 Pathwaymentioning

confidence: 99%

Autophagy Function and Regulation in Kidney Disease

et al. 2020

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Autophagy is a dynamic process by which intracellular damaged macromolecules and organelles are degraded and recycled for the synthesis of new cellular components. Basal autophagy in the kidney acts as a quality control system and is vital for cellular metabolic and organelle homeostasis. Under pathological conditions, autophagy facilitates cellular adaptation; however, activation of autophagy in response to renal injury may be insufficient to provide protection, especially under dysregulated conditions. Kidney-specific deletion of Atg genes in mice has consistently demonstrated worsened acute kidney injury (AKI) outcomes supporting the notion of a pro-survival role of autophagy. Recent studies have also begun to unfold the role of autophagy in progressive renal disease and subsequent fibrosis. Autophagy also influences tubular cell death in renal injury. In this review, we reported the current understanding of autophagy regulation and its role in the pathogenesis of renal injury. In particular, the classic mammalian target of rapamycin (mTOR)-dependent signaling pathway and other mTOR-independent alternative signaling pathways of autophagy regulation were described. Finally, we summarized the impact of autophagy activation on different forms of cell death, including apoptosis and regulated necrosis, associated with the pathophysiology of renal injury. Understanding the regulatory mechanisms of autophagy would identify important targets for therapeutic approaches.

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“…In the realm of cellular metabolism, it is known that metabolic dysfunction is a powerful organismal driving force for aging, and a senescence hallmark (123) with meaningful repercussion in diabetes (59,124). Diabetes per se is a metabolic disease in its basic origin, but that progress along with a continuous deterioration of proximal metabolic regulators such as PGC-1α, SIRT 1, and mTOR (78,79,(125)(126)(127)(128)(129)(130)(131)(132). PGC-1 plays an essential role as a master metabolic regulator as mitochondrial biogenesis and function, oxidative phosphorylation, and ROS detoxification (79).…”

Section: The Senescence Messenger Organ Metabolic Derangements and mentioning

confidence: 99%

Cellular Senescence as the Pathogenic Hub of Diabetes-Related Wound Chronicity

et al. 2020

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Diabetes is constantly increasing at a rate that outpaces genetic variation and approaches to pandemic magnitude. Skin cells physiology and the cutaneous healing response are progressively undermined in diabetes which predisposes to lower limb ulceration, recidivism, and subsequent lower extremities amputation as a frightened complication. The molecular operators whereby diabetes reduces tissues resilience and hampers the repair mechanisms remain elusive. We have accrued the notion that diabetic environment embraces preconditioning factors that definitively propel premature cellular senescence, and that ulcer cells senescence impair the healing response. Hyperglycemia/oxidative stress/mitochondrial and DNA damage may act as major drivers sculpturing the senescent phenotype. We review here historical and recent evidences that substantiate the hypothesis that diabetic foot ulcers healing trajectory, is definitively impinged by a self-expanding and self-perpetuative senescent cells society that drives wound chronicity. This society may be fostered by a diabetic archetypal secretome that induces replicative senescence in dermal fibroblasts, endothelial cells, and keratinocytes. Mesenchymal stem cells are also susceptible to major diabetic senescence drivers, which accounts for the inability of these cells to appropriately assist in diabetics wound healing. Thus, the use of autologous stem cells has not translated in significant clinical outcomes. Novel and multifaceted therapeutic approaches are required to pharmacologically mitigate the diabetic cellular senescence operators and reduce the secondary multi-organs complications. The senescent cells society and its adjunctive secretome could be an ideal local target to manipulate diabetic ulcers and prevent wound chronification and acute recidivism. This futuristic goal demands harnessing the diabetic wound chronicity epigenomic signature.

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mTORC1 senses stresses: Coupling stress to proteostasis

Cited by 69 publications

References 135 publications

Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

Deubiquitinase UCHL1 Maintains Protein Homeostasis through PSMA7-APEH-Proteasome Axis in High-Grade Serous Ovarian Carcinoma

Autophagy Function and Regulation in Kidney Disease

Cellular Senescence as the Pathogenic Hub of Diabetes-Related Wound Chronicity

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