Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome

Morselli, Eugenia; Mariño, Guillermo; Bennetzen, Martin V.; Eisenberg, Tobias; Megalou, Evgenia; Schroeder, Sabrina; Cabrera, Sandra; Bénit, Paule; Rustin, Pierre; Criollo, Alfredo; Kepp, Oliver; Galluzzi, Lorenzo; Shen, Shensi; Malik, Shoaib Ahmad; Maiuri, Maria Chiara; Horio, Yoshiyuki; López-Otı́n, Carlos; Andersen, Jens S.; Tavernarakis, Nektarios; Madeo, Frank; Kroemer, Guido

doi:10.1083/jcb.201008167

Cited by 440 publications

(383 citation statements)

References 49 publications

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“…Further supporting the preference of quinacrine for lysosomes, untreated U2OS cells exhibited a preponderant co-localization between quinacrine and an LAMP1-red fluorescent protein (RFP) fusion protein, 48 which is specifically found in lysosomes, and such colocalization was reduced upon exposure to MTX and OXA but not to rapamycin (Figures 6a and b). Concomitantly, OXA, MTX and rapamycin all promoted the co-localization of quinacrine with a RFP-LC3 chimera 49 that marks autophagosomes and autolysosomes (Figures 6c and d). Of note, the fraction of ATPrepleted (that is quinacrine þ ) LAMP1-RFP þ vesicles decreased upon the administration of OXA (Figures 6e and f).…”

Section: Panx1 Channels Operate Independently From Autophagymentioning

confidence: 89%

Molecular mechanisms of ATP secretion during immunogenic cell death

et al. 2013

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The immunogenic demise of cancer cells can be induced by various chemotherapeutics, such as anthracyclines and oxaliplatin, and provokes an immune response against tumor-associated antigens. Thus, immunogenic cell death (ICD)-inducing antineoplastic agents stimulate a tumor-specific immune response that determines the long-term success of therapy. The release of ATP from dying cells constitutes one of the three major hallmarks of ICD and occurs independently of the two others, namely, the pre-apoptotic exposure of calreticulin on the cell surface and the postmortem release of high-mobility group box 1 (HMBG1) into the extracellular space. Pre-mortem autophagy is known to be required for the ICD-associated secretion of ATP, implying that autophagy-deficient cancer cells fail to elicit therapy-relevant immune responses in vivo. However, the precise molecular mechanisms whereby ATP is actively secreted in the course of ICD remain elusive. Using a combination of pharmacological screens, silencing experiments and techniques to monitor the subcellular localization of ATP, we show here that, in response to ICD inducers, ATP redistributes from lysosomes to autolysosomes and is secreted by a mechanism that requires the lysosomal protein LAMP1, which translocates to the plasma membrane in a strictly caspase-dependent manner. The secretion of ATP additionally involves the caspase-dependent activation of Rho-associated, coiled-coil containing protein kinase 1 (ROCK1)-mediated, myosin II-dependent cellular blebbing, as well as the opening of pannexin 1 (PANX1) channels, which is also triggered by caspases. Of note, although autophagy and LAMP1 fail to influence PANX1 channel opening, PANX1 is required for the ICD-associated translocation of LAMP1 to the plasma membrane. Altogether, these findings suggest that caspase-and PANX1-dependent lysosomal exocytosis has an essential role in ATP release as triggered by immunogenic chemotherapy.

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Section: Panx1 Channels Operate Independently From Autophagymentioning

confidence: 89%

Molecular mechanisms of ATP secretion during immunogenic cell death

et al. 2013

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“…Similarly, spermidine supplied in food increases lifespan in C. elegans by 15%. This pro-longevity effect is observed in both wild-type and sir-2.1 mutant animals (although sir-2.1 lesions attenuate autophagy induction by spermidine), suggesting that, in contrast to resveratrol, lifespan extension by spermidine is independent of sir-2.1 (Morselli et al, 2011). Interfering with the autophagic machinery, by knocking down Atg7 in flies or bec-1 in worms, abolishes the beneficial effects of spermidine on lifespan for both species (Eisenberg et al, 2009).…”

Section: Pharmacological Induction Of Lifespan Extension Through Automentioning

confidence: 92%

“…Exogenous supply of spermidine induces lifespan extension in several organisms, including yeast, worms and flies. Spermidine also induces autophagy in all of these organisms and in human tumour cells (Eisenberg et al, 2009;Madeo et al, 2010;Morselli et al, 2011). Adding optimal doses of spermidine supplement in fly food, markedly increases their mean lifespan by about 30%.…”

Section: Pharmacological Induction Of Lifespan Extension Through Automentioning

confidence: 99%

“…Although resveratrol induces autophagy through SIR-2.1, which is dispensable for autophagy induction by spermidine, clearly these two compounds mediate longevity through convergent pathways. Proteomic analysis of human colon carcinoma HCT116 cells revealed that the two pathways are both AMPK and mTOR independent, whilst they induce convergent acetylproteome modifications that regulate the autophagic network (Morselli et al, 2011).…”

Section: Pharmacological Induction Of Lifespan Extension Through Automentioning

confidence: 99%

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Autophagy and ageing: Insights from invertebrate model organisms

Lionaki

Markaki

Tavernarakis

2013

Ageing Research Reviews

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a b s t r a c tAgeing in diverse species ranging from yeast to humans is associated with the gradual, lifelong accumulation of molecular and cellular damage. Autophagy, a conserved lysosomal, self-destructive process involved in protein and organelle degradation, plays an essential role in both cellular and whole-animal homeostasis. Accumulating evidence now indicates that autophagic degradation declines with age and this gradual reduction of autophagy might have a causative role in the functional deterioration of biological systems during ageing. Indeed, loss of autophagy gene function significantly influences longevity. Moreover, genetic or pharmacological manipulations that extend lifespan in model organisms often activate autophagy. Interestingly, conserved signalling pathways and environmental factors that regulate ageing, such as the insulin/IGF-1 signalling pathway and oxidative stress response pathways converge on autophagy. In this article, we survey recent findings in invertebrates that contribute to advance our understanding of the molecular links between autophagy and the regulation of ageing. In addition, we consider related mechanisms in other organisms and discuss their similarities and idiosyncratic features in a comparative manner.

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“…Typically, SIRT1 is located in the nucleus, however, SIRT1 has also been reported to be detected in the cytoplasm or mitochondria (89). In fact, SIRT1, when located in the cytoplasm, promotes autophagy and nuclear localization (90). However, SIRT2 is predominantly localized in the cytoplasm.…”

Section: Acetylation Of Foxo Proteinsmentioning

confidence: 99%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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Abstract. The Forkhead box O (FOXO) protein family is predominantly involved in apoptosis, oxidative stress, DNA damage/repair, tumor angiogenesis, glycometabolism, regulating life span and other important biological processes. Its activity is affected by a variety of posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, methylation and glycosylation. When cells are subjected to different environments, the corresponding PTMs act on the FOXO protein family, to change transcriptional activity or subcellular localization, and the expression of downstream target genes, will ultimately affect the biological behavior of the cells. In this review, we will discuss the biological characteristics of FOXO protein PTMs.

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Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome

Abstract: The acetylase inhibitor spermidine and the sirtuin-1 activator resveratrol disrupt the antagonistic network of acetylases and deacetylases that regulate autophagy.

Cited by 440 publications

References 49 publications

Molecular mechanisms of ATP secretion during immunogenic cell death

Molecular mechanisms of ATP secretion during immunogenic cell death

Autophagy and ageing: Insights from invertebrate model organisms

Post-translational modifications of FOXO family proteins

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