A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation regulates autophagy

Hu, Guowu; McQuiston, Travis; Bernard, Amélie; Park, Yoon Dong; Qiu, Jin; Vural, Ali; Zhang, Nannan; Waterman, Scott R.; Blewett, Nathan H.; Myers, Timothy G.; Maraia, Richard J; Kehrl, John H.; Uzel, Gülbû; Klionsky, Daniel J.; Williamson, Peter R.

doi:10.1038/ncb3189

Cited by 94 publications

(132 citation statements)

References 74 publications

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“…Subsequently, we determined that THP enhanced ATG4B mRNA stability in cervical cancer cells. It is known that RNA stability is affected by various factors such as RNases, 32 RNA binding proteins 33 and microRNAs. 34 A previous study has reported that MIR34A can influence the stability of ATG4B mRNA in CML progenitor cells.…”

Section: Discussionmentioning

confidence: 99%

Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin

Yan

et al. 2016

Autophagy

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Pirarubicin (THP) is a newer generation anthracycline anticancer drug. In the clinic, THP and THP-based combination therapies have been demonstrated to be effective against various tumors without severe side effects. However, previous clinical studies have shown that most patients with cervical cancer are not sensitive to THP treatment, and the associated mechanisms are not clear. Consistent with the clinical study, we confirmed that cervical cancer cells were resistant to THP in vitro and in vivo. Our data demonstrated that THP induced a protective macroautophagy/autophagy response in cervical cancer cells, and suppression of this autophagy dramatically enhanced the cytotoxicity of THP. By scanning the mRNA level change of autophagy-related genes, we found that the upregulation of ATG4B (autophagyrelated 4B cysteine peptidase) plays an important role in THP-induced autophagy. Moreover, THP increased the mRNA level of ATG4B in cervical cancer cells by promoting mRNA stability without influencing its transcription. Furthermore, THP triggered a downregulation of MIR34C-5p, which was associated with the upregulation of ATG4B and autophagy induction. Overexpression of MIR34C-5p significantly decreased the level of ATG4B and attenuated autophagy, accompanied by enhanced cell death and apoptosis in THP-treated cervical cancer cells. These results for the first time reveal the presence of a MIR34C-5p-ATG4B-autophagy signaling axis in THP-treated cervical cancer cells in vitro and in vivo, and the axis, at least partially, accounts for the THP nonsensitivity in cervical cancer patients. This study may provide a new insight for improving the chemotherapeutic effect of THP, which may be beneficial to the further clinical application of THP in cervical cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin

Yan

et al. 2016

Autophagy

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“…Dhh1/Vad1/DDX6, homologous members of the RNA helicase RCK family in S. cerevisiae , C. neoformans and mammals, respectively, can negatively regulate autophagy, along with the decapping enzyme Dcp2/DCP2 [144]. Dhh1/Vad1/DDX6 binds the 5′ untranslated region of certain transcripts and recruits Dcp2, and the enzyme is phosphorylated and activated by TOR, resulting in the decapping, further degrading specific transcripts, which maintains autophagy at a basal level [145]. However, a major unresolved question is how this small subset of transcripts is selectively targeted under growing conditions (i.e., when the vast majority of transcripts are actively translated).…”

Section: Regulation Of Autophagymentioning

confidence: 99%

An overview of macroautophagy in yeast

Wen

Klionsky

2016

Journal of Molecular Biology

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222

188

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Macroautophagy is an evolutionarily conserved dynamic pathway that functions primarily in a degradative manner. A basal level of macroautophagy occurs constitutively, but this process can be further induced in response to various types of stress including starvation, hypoxia and hormonal stimuli. The general principle behind macroautophagy is that cytoplasmic contents can be sequestered within a transient double-membrane organelle, an autophagosome, which subsequently fuses with a lysosome or vacuole (in mammals, or yeast and plants, respectively), allowing degradation of the cargo followed by recycling of the resulting macromolecules. Through this basic mechanism, macroautophagy has a critical role in cellular homeostasis; however, either insufficient or excessive macroautophagy can seriously compromise cell physiology, and thus it needs to be properly regulated. In fact, a wide range of diseases is associated with dysregulation of macroautophagy. There has been substantial progress in understanding the regulation and molecular mechanisms of macroautophagy in different organisms; however, many questions concerning some most fundamental aspects of macroautophagy still remain unresolved. In this review, we summarize current knowledge about macroautophagy mainly in yeast, including the mechanism of autophagosome biogenesis, the function of the core macroautophagic machinery, the regulation of macroautophagy, and the process of cargo recognition in selective macroautophagy, with the goal of providing insights into some of the key unanswered questions in this field.

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“…A role has recently been described for Dcp2 and RCK family RNA-binding proteins as post-transcriptional regulators of ATG mRNAs, autophagy and autophagy-dependent innate immune responses in yeast and mammalian cells (93). RCK family members-Dhh1 in S. cerevisiae, Vad1 in Cryptococcus neoformans and DDX6/p54 in mammals-are RNA helicases acting in part as decapping accessory factors that interact with target mRNAs through recruitment to the decapping complex by binding the 5' and/or 3' untranslated region of selected transcripts (reviewed in (40,94)).…”

Section: Dcp2 and Rck Family Rna Helicases Dhh1/vad1/ddx6mentioning

confidence: 99%

Transcriptional and post-transcriptional regulation of autophagy in the yeast Saccharomyces cerevisiae

Delorme-Axford

Klionsky

2018

Journal of Biological Chemistry

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Autophagy is a highly conserved catabolic pathway that is vital for development, cell survival and the degradation of dysfunctional organelles and potentially toxic aggregates. Dysregulation of autophagy is associated with cancer, neurodegeneration and lysosomal storage diseases. Accordingly, autophagy is precisely regulated at multiple levels (transcriptional, post-transcriptional, translational and post-translational) to prevent aberrant activity. Various model organisms are used to study autophagy but the baker's yeast Saccharomyces cerevisiae continues to be advantageous for genetic and biochemical analysis of non-selective and selective autophagy. In this review, we focus on the cellular mechanisms that regulate autophagy transcriptionally and post-transcriptionally in S. cerevisiae.

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A conserved mechanism of TOR-dependent RCK-mediated mRNA degradation regulates autophagy

Cited by 94 publications

References 74 publications

Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin

Targeting the MIR34C-5p-ATG4B-autophagy axis enhances the sensitivity of cervical cancer cells to pirarubicin

An overview of macroautophagy in yeast

Transcriptional and post-transcriptional regulation of autophagy in the yeast Saccharomyces cerevisiae

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