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Francesca Nazio,
Flavie Strappazzon,
Manuela Antonioli,
Pamela Bielli,
Valentina Cianfanelli,
Matteo Bordi,
Christine Gretzmeier,
Joern Dengjel, Mauro Piacentini,
Gian Maria Fimia,
Francesco Cecconi
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ABSTRACT: Autophagy is important in the basal or stress-induced clearance of bulk cytosol, damaged organelles, pathogens and selected proteins by specific vesicles, the autophagosomes. Following mTOR (mammalian target of rapamycin) inhibition, autophagosome formation is primed by the ULK1 and the beclin-1-Vps34-AMBRA1 complexes, which are linked together by a scaffold platform, the exocyst. Although several regulative steps have been described along this pathway, few targets of mTOR are known, and the cross-talk between ULK1 and beclin 1 complexes is still not fully understood. We show that under non-autophagic conditions, mTOR inhibits AMBRA1 by phosphorylation, whereas on autophagy induction, AMBRA1 is dephosphorylated. In this condition, AMBRA1, interacting with the E3-ligase TRAF6, supports ULK1 ubiquitylation by LYS-63-linked chains, and its subsequent stabilization, self-association and function. As ULK1 has been shown to activate AMBRA1 by phosphorylation, the proposed pathway may act as a positive regulation loop, which may be targeted in human disorders linked to impaired autophagy.
Nature Cell Biology 03/2013; · 19.49 Impact Factor
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ABSTRACT: Tuberculosis is a global health calamity. The causative agent, Mycobacterium tuberculosis (M. tuberculosis), has evolved elaborate survival mechanisms in humans, allowing it to remain in a clinically latent infection state, constantly engaging the immune system, with the possibility to progress to active disease. Autophagy is a cellular process responsible for the degradation of intracellular components, including invading pathogens, playing an important role in both innate and adaptive immunity. In this review, we describe the molecular mechanisms employed by M. tuberculosis to avoid autophagic degradation and exploit this process to its own advantage. Moreover, we discuss the multiple roles played by autophagy in the immune responses to M. tuberculosis, and its unforeseen contribution to the antibacterial activity of tuberculosis-specific drugs.
Cytokine & growth factor reviews 02/2013; · 6.49 Impact Factor
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ABSTRACT: AMBRA1 is a positive regulator of the BECN1-dependent program of autophagy recently identified in mouse. In this study, we cloned the full-length cDNAs of ambra1a and ambra1b zebrafish paralogous genes. As in mouse, both Ambra1 proteins contain the characteristic WD40 repeat region. The transcripts of both genes are present as maternal RNAs in the eggs and display a gradual decline until 8 hpf, being replaced by zygotic mRNAs from 12 hpf onwards. After 24 hpf, the transcripts are mainly localized in the head, suggesting a possible role in brain development. To check their developmental roles, we adopted morpholino knockdown to block either translation (ATGMOs) or splicing (SPLICMOs). Treatment with ATGMOs causes severe embryonic malformations, as prelarvae could survive for only 3 and 4 days in ambra1a and b morphants, respectively. Treatment with SPLICMOs led to developmental defects only at a late stage, indicating the importance of maternally supplied ambra1 transcripts. Analysis of the levels of Lc3-II, an autophagosome-specific marker, in the presence of lysosome inhibitors evidenced a reduction in the rate of autophagosome formation in both MOs-injected embryos at 48 hpf, more pronounced in the case of ambra1a gene. Although some defects, such as body growth delay, curved shape and hemorrhagic pericardial cavity were present in both morphants, the occurrence of specific phenotypes, such as major abnormalities of brain development in ambra1a morphants, suggests the possible acquisition of specific functions by the two paralogous genes that are both required during development and do not compensate each other following knockdown.
Autophagy 01/2013; 9(4). · 7.45 Impact Factor
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Reproduction Fertility and Development 11/2012; · 2.11 Impact Factor
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Laura Senovilla,
Ilio Vitale,
Isabelle Martins,
Maximilien Tailler,
Claire Pailleret,
Mickaël Michaud,
Lorenzo Galluzzi,
Sandy Adjemian,
Oliver Kepp,
Mireia Niso-Santano, [......],
Christoph Ruckenstuhl,
Didac Carmona-Gutierrez,
Vladimir Lazar,
Josef M Penninger,
Frank Madeo,
Carlos López-Otín,
Mark J Smyth,
Laurence Zitvogel,
Maria Castedo,
Guido Kroemer
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ABSTRACT: Cancer cells accommodate multiple genetic and epigenetic alterations that initially activate intrinsic (cell-autonomous) and extrinsic (immune-mediated) oncosuppressive mechanisms. Only once these barriers to oncogenesis have been overcome can malignant growth proceed unrestrained. Tetraploidization can contribute to oncogenesis because hyperploid cells are genomically unstable. We report that hyperploid cancer cells become immunogenic because of a constitutive endoplasmic reticulum stress response resulting in the aberrant cell surface exposure of calreticulin. Hyperploid, calreticulin-exposing cancer cells readily proliferated in immunodeficient mice and conserved their increased DNA content. In contrast, hyperploid cells injected into immunocompetent mice generated tumors only after a delay, and such tumors exhibited reduced DNA content, endoplasmic reticulum stress, and calreticulin exposure. Our results unveil an immunosurveillance system that imposes immunoselection against hyperploidy in carcinogen- and oncogene-induced cancers.
Science 09/2012; 337(6102):1678-84. · 31.20 Impact Factor
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Alessandra Romagnoli,
Marilena P Etna,
Elena Giacomini,
Manuela Pardini,
Maria Elena Remoli,
Marco Corazzari,
Laura Falasca,
Delia Goletti,
Valérie Gafa,
Roxane Simeone,
Giovanni Delogu, Mauro Piacentini,
Roland Brosch,
Gian Maria Fimia,
Eliana M Coccia
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ABSTRACT: Emerging evidence points to an important role of autophagy in the immune response mediated by dendritic cells (DC) against Mycobacterium tuberculosis (Mtb). Since current vaccination based on Bacillus Calmette-Guerin (BCG) is unable to stop the tuberculosis epidemic, a deeper comprehension of the alterations induced by Mtb in DC is essential for setting new vaccine strategies. Here, we compared the capacity of virulent (H37Rv) and avirulent (H37Ra) Mtb strains as well as BCG to modulate autophagy in human primary DC. We found that Mtb H37Rv impairs autophagy at the step of autophagosome-lysosome fusion. In contrast, neither Mtb H37Ra nor BCG strains were able to hamper autophagosome maturation. Both these attenuated strains have a functional inhibition of the 6kD early secreted antigenic target ESAT-6, an effector protein of the ESAT-6 Secretion System-1(ESX-1)/type VII secretion system. Notably, the ability to inhibit autophagy was fully restored in recombinant BCG and Mtb H37Ra strains in which ESAT-6 secretion was re-established by genetic complementation using either the ESX-1 region from Mtb (BCG::ESX-1) or the PhoP gene (Mtb H37Ra::PhoP), a regulator of ESAT-6 secretion. Importantly, the autophagic block induced by Mtb was overcome by rapamycin treatment leading to an increased interleukin-12 expression and, in turn, to an enhanced capacity to expand a Th1-oriented response. Collectively, our study demonstrated that Mtb alters the autophagic machinery through the ESX-1 system, and thereby opens new exciting perspectives to better understand the relationship between Mtb virulence and its ability to escape the DC-mediated immune response.
Autophagy 09/2012; 8(9):1357-70. · 7.45 Impact Factor
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ABSTRACT: Under stress conditions cells activate different response pathways which result in cell survival or apoptosis depending on: (1) the nature of the insults, (2) the type, if acute or chronic stress, and (3) how long the stress persists. Generally, autophagy is induced early to sustain cell survival and inhibit cell death. However, adverse conditions are able to overcome autophagy to promote cell death. Increasing evidence suggests that the inhibition of autophagy by the apoptotic machinery has been proposed as one of the crucial events responsible for the irreversible switch from survival to death. The mechanism seems to be related to the selective apoptotic protease-mediated degradation of key autophagic proteins. We recently found that AMBRA1, an important regulator of the autophagic process mediating the initial steps of autophagosome formation, is also irreversibly degraded by the combined activity of caspases and calpains. This phenomenon is not merely a consequence of apoptosis execution but represents a key step required to efficiently promote the autophagic vs apoptosis switch.
Autophagy 08/2012; 8(8):1255-7. · 7.45 Impact Factor
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Amino Acids 07/2012; · 3.25 Impact Factor
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Daniel J Klionsky,
Fabio C Abdalla,
Hagai Abeliovich,
Robert T Abraham,
Abraham Acevedo-Arozena,
Khosrow Adeli,
Lotta Agholme,
Maria Agnello,
Patrizia Agostinis,
Julio A Aguirre-Ghiso, [......],
Changlian Zhu,
Wei-Guo Zhu,
Xiao-Feng Zhu,
Xiongwei Zhu,
Yuangang Zhu,
Teresa Zoladek,
Wei-Xing Zong,
Antonio Zorzano,
Jürgen Zschocke,
Brian Zuckerbraun
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ABSTRACT: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
Autophagy 04/2012; 8(4):445-544. · 7.45 Impact Factor
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ABSTRACT: Autophagy inhibits survival of intracellular Mycobacterium tuberculosis when induced by rapamycin or interferon γ (IFN-γ), but it remains unclear whether M. tuberculosis itself can induce autophagy and whether T cells play a role in M. tuberculosis-mediated autophagy. The aim of this study was to evaluate the impact of M. tuberculosis on autophagy in human primary macrophages and the role of specific T cells in this process.
M. tuberculosis (H37Rv)-infected macrophages were incubated with naive or M. tuberculosis-specific T cells. Autophagy was evaluated at 4 hours and 8 hours after infection by analyzing the levels of LC3-II (a hallmark of autophagy) and p62 (a protein degraded by autophagy). M. tuberculosis survival was evaluated by counting the colony-forming units.
M. tuberculosis infection of macrophages inhibited the autophagic process at 8 hours after infection. Naive T cells could not rescue this block, whereas M. tuberculosis-specific T cells restored autophagy degradation, accompanied by enhanced bacterial killing. Notably, the effect of M. tuberculosis-specific T cells was not affected by neutralization of endogenous IFN-γ and tumor necrosis factor α and was blocked by preventing contact between macrophages and T cells, suggesting that cell-cell interaction is crucial.
M. tuberculosis inhibits autophagy in human primary macrophages, and specific T cells can restore functional autophagic flux through cell-cell contact.
The Journal of Infectious Diseases 03/2012; 205(9):1425-35. · 6.41 Impact Factor
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ABSTRACT: The endoplasmic reticulum (ER) consists of the nuclear envelope and a peripheral network of tubules and membrane sheets. The tubules are shaped by a specific class of curvature stabilizing proteins, the reticulons and DP1; however it is still unclear how the sheets are assembled. The ER is the cellular compartment responsible for secretory and membrane protein synthesis. The reducing conditions of ER lead to the intra/inter-chain formation of new disulphide bonds into polypeptides during protein folding assessed by enzymatic or spontaneous reactions. Moreover, ER represents the main intracellular calcium storage site and it plays an important role in calcium signaling that impacts many cellular processes. Accordingly, the maintenance of ER function represents an essential condition for the cell, and ER morphology constitutes an important prerogative of it. Furthermore, it is well known that ER undergoes prominent shape transitions during events such as cell division and differentiation. Thus, maintaining the correct ER structure is an essential feature for cellular physiology. Now, it is known that proper ER-associated proteins play a fundamental role in ER tubules formation. Among these ER-shaping proteins are the reticulons (RTN), which are acquiring a relevant position. In fact, beyond the structural role of reticulons, in very recent years new and deeper functional implications of these proteins are emerging in relation to their involvement in several cellular processes.
Experimental Cell Research 03/2012; 318(11):1201-7. · 3.58 Impact Factor
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ABSTRACT: Beclin1(Atg6) is a well-known key regulator of autophagy. Although Beclin1 is enzymatically inert, it governs the autophagic process by regulating PtdIns3KC3-dependent generation of phosphatidylinositol3-phosphate (PtdIns(3)P) and the subsequent recruitment of additional Atg proteins that orchestrate autophagosome formation. Furthermore, Beclin1 is implicated in numerous biological processes, including adaptation to stress, development, endocytosis, cytokinesis, immunity, tumorigenesis, ageing and cell death. Whether all of these processes involve only the autophagy-inducing function of Beclin1 is now being seriously questioned, because Beclin1 appears to exercise several non-autophagy functions. Therefore, we should broaden our view of Beclin1 as a specialized molecule in autophagy to that of a multifunctional protein. The central role of Beclin1 in multiple signaling events obviously requires tight regulation at multiple levels. Its function is kept in check by diverse mechanisms, such as epigenetic silencing, microRNA regulation, post-translational modifications, and protein-protein interactions. Interestingly, multiple diseases are associated with deficiency or malfunction of Beclin1, which makes it a potentially valuable target for various therapies, including anti-cancer treatment. In this review, we focus on Beclin1 as a multifunctional protein, discuss the variety of mechanisms by which it is controlled, and give an overview of Beclin1-associated pathologies.
Autophagy 01/2012; 8(1):6-17. · 7.45 Impact Factor
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ABSTRACT: Reticulons (RTNs) are a group of membrane proteins localized on the ER and known to regulate ER structure and functions. Several studies have suggested that RTNs are involved in different important cellular functions such as changes in calcium homeostasis, ER-stress-mediated cell death, and autophagy. RTNs have been demonstrated to exert a cancer specific proapoptotic function via the interaction or the modulation of specific proteins. Reticulons have also been implicated in different signaling pathways which are at the basis of the pathogenesis of several neurodegenerative diseases. In this paper we discuss the accumulating evidence identifying RTN-1C protein as a promising target in the treatment of different pathologies such as cancer or neurodegenerative disorders.
International Journal of Cell Biology 01/2012; 2012:651805.
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Tiziana Vescovo,
Alessandra Romagnoli,
Ariel Basulto Perdomo,
Marco Corazzari,
Fabiola Ciccosanti,
Tonino Alonzi,
Roberta Nardacci,
Giuseppe Ippolito,
Marco Tripodi,
Carmelo Garcia-Monzon,
Oreste Lo Iacono, Mauro Piacentini,
Gian Maria Fimia
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ABSTRACT: Autophagy is a lysosome-mediated catabolic process that mediates degradation and recycling of all major components of eukaryotic cells. Different stresses, including viral and bacterial infection, induce autophagy, which can promote cell survival by removing the stress inducer or by attenuating its dangerous effects. High levels of autophagy occur during infection of cells with hepatitis C virus (HCV), but the clinical relevance of this process is not clear.
Levels of autophagy were analyzed in liver biopsy samples from 22 patients with HCV infection using microtubule-associated protein-1 light chain 3 immunoblotting; associations with histological and metabolic parameters were evaluated by Pearson correlation analysis. We investigated the role of HCV-induced autophagy in lipid degradation in cells infected with the virus or replicons, and analyzed autophagosome contents by confocal microscopy and by measuring lipid levels after inhibition of autophagy by Beclin 1 knockdown or lysosome inhibitors.
In liver biopsy samples from patients with HCV, there was an inverse correlation between microvesicular steatosis and level of autophagy (r = -0.617; P = .002). HCV selectively induced autophagy of lipids in virus-infected and replicon cells. In each system, autophagosomes frequently colocalized with lipid deposits, mainly formed by unesterified cholesterol. Inhibition of the autophagic process in these cells significantly increased the induction of cholesterol accumulation by HCV.
Autophagy counteracts the alterations in lipid metabolism induced by HCV. Disruption of the autophagic process might contribute to development of steatosis in patients with HCV.
Gastroenterology 12/2011; 142(3):644-653.e3. · 11.68 Impact Factor
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Ariel Basulto Perdomo,
Fabiola Ciccosanti,
Oreste Lo Iacono,
Claudio Angeletti,
Marco Corazzari,
Nicola Daniele,
Angela Testa,
Roberto Pisa,
Giuseppe Ippolito,
Giorgio Antonucci,
Gian Maria Fimia, Mauro Piacentini
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ABSTRACT: The current anti-hepatitis C virus (HCV) therapy, based on pegylated-interferon alpha and ribavirin, has limited success rate and is accompanied by several side effects. The aim of this study was to identify protein profiles in pretreatment liver biopsies of HCV patients correlating with the outcome of antiviral therapy. Cytosolic or membrane/organelle-enriched protein extracts from liver biopsies of eight HCV patients were analyzed by two-dimensional fluorescence difference gel electrophoresis and mass spectrometry. Overall, this analysis identified 21 proteins whose expression levels correlate with therapy response. These factors are involved in interferon-mediated antiviral activity, stress response, and energy metabolism. Moreover, we found that post-translational modifications of dihydroxyacetone kinase were also associated with therapy outcome. Differential expression of the five best performing markers (STAT1, Mx1, DD4, DAK, and PD-ECGF) was confirmed by immunoblotting assays in an independent group of HCV patients. Finally, we showed that a prediction model based on the expression levels of these markers classifies responder and nonresponder patients with an accuracy of 85.7%. These results provide evidence that the analysis of pretreatment liver protein profiles is valuable for discriminating between responder and nonresponder HCV patients, and may contribute to reduce the number of nonresponder patients exposed to therapy-associated risks.
Journal of Proteome Research 11/2011; 11(2):717-27. · 5.11 Impact Factor
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10/2011: pages 197 - 246; , ISBN: 9781118105771
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Claire Séror,
Marie-Thérèse Melki,
Frédéric Subra,
Syed Qasim Raza,
Marlène Bras,
Héla Saïdi,
Roberta Nardacci,
Laurent Voisin,
Audrey Paoletti,
Frédéric Law, [......],
Laura Falasca,
Rita Casetti,
Nazanine Modjtahedi,
Jean Kanellopoulos,
Jean-François Mouscadet,
David M Ojcius, Mauro Piacentini,
Marie-Lise Gougeon,
Guido Kroemer,
Jean-Luc Perfettini
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ABSTRACT: Extracellular adenosine triphosphate (ATP) can activate purinergic receptors of the plasma membrane and modulate multiple cellular functions. We report that ATP is released from HIV-1 target cells through pannexin-1 channels upon interaction between the HIV-1 envelope protein and specific target cell receptors. Extracellular ATP then acts on purinergic receptors, including P2Y2, to activate proline-rich tyrosine kinase 2 (Pyk2) kinase and transient plasma membrane depolarization, which in turn stimulate fusion between Env-expressing membranes and membranes containing CD4 plus appropriate chemokine co-receptors. Inhibition of any of the constituents of this cascade (pannexin-1, ATP, P2Y2, and Pyk2) impairs the replication of HIV-1 mutant viruses that are resistant to conventional antiretroviral agents. Altogether, our results reveal a novel signaling pathway involved in the early steps of HIV-1 infection that may be targeted with new therapeutic approaches.
Journal of Experimental Medicine 08/2011; 208(9):1823-34. · 13.85 Impact Factor
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ABSTRACT: Tissue transglutaminase (TG2) activity has been implicated in inflammatory disease processes such as Celiac disease, infectious diseases, cancer, and neurodegenerative diseases, such as Huntington's disease. Furthermore, four distinct biochemical activities have been described for TG2 including protein crosslinking via transamidation, GTPase, kinase and protein disulfide isomerase activities. Although the enzyme plays a complex role in the regulation of cell death and autophagy, the molecular mechanisms and the putative biochemical activity involved in each is unclear. Therefore, the goal of the present study was to determine how TG2 modulates autophagy and/or apoptosis and which of its biochemical activities is involved in those processes. To address this question, immortalized embryonic fibroblasts obtained from TG2 knock-out mice were reconstituted with either wild-type TG2 or TG2 lacking its transamidating activity and these were subjected to different treatments to induce autophagy or apoptosis. We found that knock out of the endogenous TG2 resulted in a significant exacerbation of caspase 3 activity and PARP cleavage in MEF cells subjected to apoptotic stimuli. Interestingly, the same cells showed the accumulation of LC3 II isoform following autophagy induction. These findings strongly suggest that TG2 transamidating activity plays a protective role in the response of MEF cells to death stimuli, because the expression of the wild-type TG2, but not its transamidation inactive C277S mutant, resulted in a suppression of caspase 3 as well as PARP cleavage upon apoptosis induction. Additionally, the same mutant was unable to catalyze the final steps in autophagosome formation during autophagy. Our findings clearly indicate that the TG2 transamidating activity is the primary biochemical function involved in the physiological regulation of both apoptosis and autophagy. These data also indicate that TG2 is a key regulator of cross-talk between autophagy and apoptosis.
Amino Acids 04/2011; 42(5):1793-802. · 3.25 Impact Factor
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ABSTRACT: The demonstration that type 2 transglutaminase (TG2) can incorporate polyamine into the E7 oncoprotein of human papillomavirus (HPV) type 18 has led to the hypothesis that TG2 can have a role in the host cellular response to HPV infection. The aim of this study was to investigate whether HPV-related pathology, in infected human cervical epithelium, was associated with modulation of TG2 expression. Normal controls and HPV-infected cervical biopsies were analyzed for the expression of TG2, and the findings were compared with lesion grade. The correlation between TG2 expression and p16, a marker for HPV-induced dysplasia, and the retinoblastoma protein (Rb), a target of the E7 protein of HPV, was also investigated. Results obtained showed that TG2 was absent in normal squamous mucosa, whereas it was present in 100% CIN I lesions. Low-grade lesions showed significantly higher TG2 expression than high-grade lesions (P<0.0001). In 94% of CIN I more than 50% of the cells were positive for TG2, with a strong staining intensity (+3), whereas a decreased staining intensity and a low number of positive cells were found in CIN II/III. In CIN I cases, both nuclear and cytoplasmic staining were found in cells exhibiting classical morphological features of HPV infection. In addition, during progression from low-grade squamous intraepithelial lesions to severe dysplasia, TG2 expression was inversely correlated with p16 (Pearson: -0.930), whereas a positive correlation was observed between the expression of TG2 and pRb (Pearson: 0.997). TG2 is expressed in HPV infection as an early phenomenon, not restricted to high-risk genotypes. TG2 upregulation is probably part of host cell reaction against HPV-induced tissue modification. It may act as a cellular antioxidant defense factor, playing an important role in counteracting oxidative damage in neoplastic disease.
Modern Pathology 03/2011; 24(6):855-65. · 4.79 Impact Factor
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ABSTRACT: BECLIN 1 is a central player in macroautophagy. AMBRA1, a BECLIN 1-interacting protein, positively regulates the BECLIN 1-dependent programme of autophagy. In this study, we show that AMBRA1 binds preferentially the mitochondrial pool of the antiapoptotic factor BCL-2, and that this interaction is disrupted following autophagy induction. Further, AMBRA1 can compete with both mitochondrial and endoplasmic reticulum-resident BCL-2 (mito-BCL-2 and ER-BCL-2, respectively) to bind BECLIN 1. Moreover, after autophagy induction, AMBRA1 is recruited to BECLIN 1. Altogether, these results indicate that, in normal conditions, a pool of AMBRA1 binds preferentially mito-BCL-2; after autophagy induction, AMBRA1 is released from BCL-2, consistent with its ability to promote BECLIN 1 activity. In addition, we found that the binding between AMBRA1 and mito-BCL-2 is reduced during apoptosis. Thus, a dynamic interaction exists between AMBRA1 and BCL-2 at the mitochondria that could regulate both BECLIN 1-dependent autophagy and apoptosis.
The EMBO Journal 02/2011; 30(7):1195-208. · 9.20 Impact Factor
