Rubicon in Metabolic Diseases and Ageing

Minami, Satoshi; Nakamura, Shuhei; Yoshimori, Tamotsu

doi:10.3389/fcell.2021.816829

Cited by 9 publications

(4 citation statements)

References 66 publications

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“…In autophagy, class III phosphatidylinositol-3-kinase (PI3KC3), which consists of three core components (Vps34, p150, Beclin-1), plays an important role in autophagosome biogenesis by catalyzing the formation of phosphatidylinositol-3-phosphate 47) . Rubicon directly binds with PI3KC3-related components and suppresses their function, resulting in inhibition of autophagosome-lysosome fusion processes 48) . However, overexpression of Rubicon leads to autophagy impairment in senescent cells.…”

Section: Discussionmentioning

confidence: 99%

Etoposide-Induced Cellular Senescence Suppresses Autophagy in Human Keratinocytes

Yoshida,

Takahashi,

Tsuchimochi

et al. 2023

J. hard tissue biol.

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Autophagy and senescence play important roles in cellular homeostasis. However, it remains unknown whether autophagy positively or negatively affects cellular senescence. We cultured human keratinocytes (HaCaT) with or without etoposide (ETO) treatment to examine whether autophagy mediates induction of DNA damage response (DDR)-related cellular senescence. DDR-related cellular senescence was observed in 5.0-μM ETO-treated cells through increased expression of γH2AX, p53 binding protein1 (53BP1), and senescence-associated β-galactosidase (SA-β-Gal), whereas no senescent changes were observed in 1.0-μM ETO-treated cells. Senescent cells also showed increased expression of activated ataxiatelangiectasia mutated (ATM) signaling pathway-related factor, such as pATM, pp53, and p21. The 5.0-μM ETO-treated senescent cells showed downregulated expression of LC3 and Beclin-1, but expression of Rubicon, which is a negative regulator of autophagy, was upregulated even though no senescent-induced cells (1.0-μM treated cells) revealed increased expression of LC3 and Beclin-1. The 1.0-μM ETO-treated cells pretreated with N-acetylcysteine (NAC) showed increased expression of senescent markers and p21 as well as Rubicon. This study revealed that Rubicon-regulated autophagy mediates ETO-induced DDR-related cellular senescence through the activation of the ATM/p53/p21 signaling pathway. Impaired autophagy due to Rubicon overexpression accelerates induction of DDR-related cellular senescence.

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Section: Discussionmentioning

confidence: 99%

Etoposide-Induced Cellular Senescence Suppresses Autophagy in Human Keratinocytes

Yoshida,

Takahashi,

Tsuchimochi

et al. 2023

J. hard tissue biol.

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“…Elevated levels of Rubicon have been previously correlated with a reduction in autophagy activity in several cells, including neurons [ 28 ], cardiomyocytes [ 59 , 60 ], hepatocytes [ 61 ], adipocytes [ 62 , 63 ], and retinal epithelium [ 64 ]. Crescent Rubicon levels during aging have been associated with the decline in autophagy activity, arising as one of the potential target molecules in aging [ 28 , 29 , 65 ]. A recent study reported some components of this potential pathway [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease

Espinoza

Grunenwald

Gómez

et al. 2022

Cells

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Alzheimer’s disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon’s role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid β burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid β burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid β secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP/amyloid β homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid β secretion, defining a new way to target AD and other similar diseases therapeutically.

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“…Notably, autosis is associated with reduced autophagic flux, blockade of autophagosome clearance and upregulation of Rubicon (RUN domain Beclin-1 interacting and cysteine-rich-containing protein) (11). Rubicon is one of the few endogenous inhibitors of autophagy during autophagosome maturation and autophagosome-lysosome fusion (12,13). Rubicon has been also involved in autophagy-independent functions including LAP (LC3-associated phagocytosis), endosomal trafficking and inflammatory responses (14-16).…”

Section: Introductionmentioning

confidence: 99%

Plasma levels of autophagy regulator Rubicon are inversely associated with acute coronary syndrome

Grazide,

Ruidavets,

Martinet

et al. 2024

Front. Cardiovasc. Med.

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BackgroundThe discovery of novel biomarkers that improve current cardiovascular risk prediction models of acute coronary syndrome (ACS) is needed for the identification of very high-risk patients and therapeutic decision-making. Autophagy is a highly conserved catabolic mechanism for intracellular degradation of cellular components through lysosomes. The autophagy process helps maintain cardiac homeostasis and dysregulated autophagy has been described in cardiovascular conditions. Rubicon (Run domain Beclin-1-interacting and cysteine-rich domain-containing protein) is a key regulator of autophagy with a potential role in cardiac stress.ObjectivesThe aims of the present study were to assess whether changes in circulating Rubicon levels are associated with ACS and to evaluate the added value of Rubicon to a clinical predictive risk model.Methods and resultsThe study population included ACS patients (n = 100) and control subjects (n = 99) at high to very high cardiovascular risk but without known coronary event. Plasma Rubicon levels were measured in the whole study population by enzyme-linked immunosorbent assay. Multivariate logistic regression analyses established that Rubicon levels were inversely associated with ACS. A receiver operating characteristic curve analysis demonstrated that the addition of Rubicon improved the predictive performance of the model with an increased area under the curve from 0.868 to 0.896 (p = 0.038).ConclusionsPlasma levels of the autophagy regulator Rubicon are associated with ACS and provide added value to classical risk markers for ACS.

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Rubicon in Metabolic Diseases and Ageing

Cited by 9 publications

References 66 publications

Etoposide-Induced Cellular Senescence Suppresses Autophagy in Human Keratinocytes

Etoposide-Induced Cellular Senescence Suppresses Autophagy in Human Keratinocytes

Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease

Plasma levels of autophagy regulator Rubicon are inversely associated with acute coronary syndrome

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