The autophagic roles of Rab small GTPases and their upstream regulators

Szatmári, Zsuzsanna; Sass, Miklós

doi:10.4161/auto.29395

Cited by 135 publications

(119 citation statements)

References 122 publications

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“…Thus far about 10 known Rab proteins are found to regulate autophagy, among which only Rab7 has a defined role in late stage of autophagy [40]. In addition, many Rab members, including Rab7, play important roles in invasiveness and metastasis in cancers [32,41].…”

Section: Discussionmentioning

confidence: 99%

Impact of Autophagy Inhibition at Different Stages on Cytotoxic Effect of Autophagy Inducer in Glioblastoma Cells

Liu²,

Liu³

et al. 2015

Cell Physiol Biochem

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Background/Aims: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor with a poor prognosis. Combination treatment of autophagy inducer and autophagy inhibitor may be a feasible solution to improve the therapeutic effects. However, the correlation between them is unclear. The purpose of this study was to investigate the effect of autophagy inhibition at different stages on cytotoxicity of autophagy inducers in glioblastoma cells. Methods: Autophagy inhibition at early stage was achieved by 3-methyladenine (3-MA) or Beclin 1 shRNA. Autophagy inhibition at late stage was achieved by chloroquine (CQ) or Rab7 shRNA. Cell viability was assessed by MTT assay. Autophagy was measured using transmission electron microscopy and western blot. Apoptosis was measured using western blot and flow-cytometry. Results: Inhibition of early steps of autophagy by 3-MA or Beclin 1 knockdown decreased the toxic effect of arsenic trioxide (ATO) in GBM cell lines. In contrast, blockade of autophagy flux at late stage by CQ or Rab7 knockdown enhanced the cytotoxicity of ATO, and caused accumulation of degradative autophagic vacuoles and robust apoptosis. Moreover, depletion of Beclin 1 abolished the synergistic effect of ATO and CQ by reducing autophagy and apoptosis. Combination of CQ with other autophagy inducers also induced synergistic apoptotic cell death. Conclusion: These results suggest that inhibition of late process of autophagy, not initial step, increases the cytotoxic effect of autophagy inducers via autophagy and apoptosis, which may contribute to GBM chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Impact of Autophagy Inhibition at Different Stages on Cytotoxic Effect of Autophagy Inducer in Glioblastoma Cells

Liu²,

Liu³

et al. 2015

Cell Physiol Biochem

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“…Rab and SNARE proteins also regulate lysosome fusion with MVBs and autophagosomes (Szatmari and Sass 2014). The mechanism of the fusion is not completely characterized yet, but it has been shown to involve Rab7 and Rab11 and the SNARE proteins VAMP7, VAMP3, VAMP8, syntaxin 11, syntaxin 8, HOPS, NSF and vti1b (Huotari and Helenius 2011, Luzio, Hackmann et al 2014, Szatmari, Kis et al 2014).…”

Section: Exosome Biogenesismentioning

confidence: 99%

Impact of lysosome status on extracellular vesicle content and release

Eitan

Suire

Shi

et al. 2016

Ageing Research Reviews

210

161

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Extracellular vesicles (EVs) are nanoscale size bubble-like membranous structures released from cells. EVs contain RNA, lipids and proteins and are thought to serve various roles including intercellular communication and removal of misfolded proteins. The secretion of misfolded and aggregated proteins in EVs may be a cargo disposal alternative to the autophagy-lysosomal and ubiquitin-proteasome pathways. In this review we will discuss the importance of lysosome functionality for the regulation of EV secretion and content. Exosomes are a subtype of EVs that are released by the fusion of multivesicular bodies (MVB) with the plasma membrane. MVBs can also fuse with lysosomes, and the trafficking pathway of MVBs can therefore determine whether or not exosomes are released from cells. Here we summarize data from studies of the effects of lysosome inhibition on the secretion of EVs and on the possibility that cells compensate for lysosome malfunction by disposal of potentially toxic cargos in EVs. A better understanding of the molecular mechanisms that regulate trafficking of MVBs to lysosomes and the plasma membrane may advance an understanding of diseases in which pathogenic proteins, lipids or infectious agents accumulate within or outside of cells.

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“…For example, autolysosome formation and the trafficking of MVBs to lysosomes are processes regulated by LE-associated proteins, among which the small GTPase, Rab7A, a critical regulator of endosomal maturation/functionality (81–83) and syntaxin 5 (84). Moreover, endosomal membranes can contribute to the formation of autophagosomes through vesicles derived from Rab11-positive recycling endosomes, where both ULK1 and mATG9 reside and sense autophagy induction (85).…”

Section: The Proteome Under Control: a Brief Overview Of Key Pathwaysmentioning

confidence: 99%

Adapt, Recycle, and Move on: Proteostasis and Trafficking Mechanisms in Melanoma

et al. 2016

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Melanoma has emerged as a paradigm of a highly aggressive and plastic cancer, capable to co-opt the tumor stroma in order to adapt to the hostile microenvironment, suppress immunosurveillance mechanisms, and disseminate. In particular, oncogene- and aneuploidy-driven dysregulations of proteostasis in melanoma cells impose a rewiring of central proteostatic processes, such as the heat shock and unfolded protein responses, autophagy, and the endo-lysosomal system, to avoid proteotoxicity. Research over the past decade has indicated that alterations in key nodes of these proteostasis pathways act in conjunction with crucial oncogenic drivers to increase intrinsic adaptations of melanoma cells against proteotoxic stress, modulate the high metabolic demand of these cancer cells and the interface with other stromal cells, through the heightened release of soluble factors or exosomes. Here, we overview and discuss how key proteostasis pathways and vesicular trafficking mechanisms are turned into vital conduits of melanoma progression, by supporting cancer cell’s adaptation to the microenvironment, limiting or modulating the ability to respond to therapy and fueling melanoma dissemination.

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The autophagic roles of Rab small GTPases and their upstream regulators

Cited by 135 publications

References 122 publications

Impact of Autophagy Inhibition at Different Stages on Cytotoxic Effect of Autophagy Inducer in Glioblastoma Cells

Impact of Autophagy Inhibition at Different Stages on Cytotoxic Effect of Autophagy Inducer in Glioblastoma Cells

Impact of lysosome status on extracellular vesicle content and release

Adapt, Recycle, and Move on: Proteostasis and Trafficking Mechanisms in Melanoma

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