Table of Contents

Volume 8, Issue 5

  May 2012

  Pages 715 - 866

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 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

Autophagy contributes to lysosomal storage disorders

Yohta Shimada and Daniel J. Klionsky
Pages 715 - 716
http://dx.doi.org/10.4161/auto.19920
Abstract | Full Text | PDF

Degradation in the lysosome/vacuole is not the final step of autophagy. In particular, for starvation-induced autophagy it is necessary to release the breakdown products back into the cytosol. However, some researchers ignore this last step and simply refer to the endpoint of autophagy as degradation, or perhaps even cargo delivery. In many cases this is not a serious issue; however, the analysis of autophagy’s role in certain diseases makes clear that this can be a significant error.




AUTOPHAGIC FLUX

Open Access Article

Highlights from this issue

Andriy Nemchenko
Pages 717 - 718
http://dx.doi.org/10.4161/auto.20701
Full Text | PDF




REVIEW

Open Access Article

Autophagy in lysosomal storage disorders

Andrew P. Lieberman, Rosa Puertollano, Nina Raben, Susan Slaugenhaupt, Steven U. Walkley and Andrea Ballabio
Pages 719 - 730
http://dx.doi.org/10.4161/auto.19469
Abstract | Full Text | PDF

Lysosomes are ubiquitous intracellular organelles that have an acidic internal pH, and play crucial roles in cellular clearance. Numerous functions depend on normal lysosomes, including the turnover of cellular constituents, cholesterol homeostasis, downregulation of surface receptors, inactivation of pathogenic organisms, repair of the plasma membrane and bone remodeling. Lysosomal storage disorders (LSDs) are characterized by progressive accumulation of undigested macromolecules within the cell due to lysosomal dysfunction. As a consequence, many tissues and organ systems are affected, including brain, viscera, bone and cartilage. The progressive nature of phenotype development is one of the hallmarks of LSDs. In recent years biochemical and cell biology studies of LSDs have revealed an ample spectrum of abnormalities in a variety of cellular functions. These include defects in signaling pathways, calcium homeostasis, lipid biosynthesis and degradation and intracellular trafficking. Lysosomes also play a fundamental role in the autophagic pathway by fusing with autophagosomes and digesting their content. Considering the highly integrated function of lysosomes and autophagosomes it was reasonable to expect that lysosomal storage in LSDs would have an impact upon autophagy. The goal of this review is to provide readers with an overview of recent findings that have been obtained through analysis of the autophagic pathway in several types of LSDs, supporting the idea that LSDs could be seen primarily as “autophagy disorders.”




BASIC BRIEF REPORT

Open Access Article

Autophagy proteins play cytoprotective and cytocidal roles in leucine starvation-induced cell death in Saccharomyces cerevisiae

Slawomir A. Dziedzic and Allan B. Caplan
Pages 731 - 738
http://dx.doi.org/10.4161/auto.19314
Abstract | Full Text | PDF

Autophagy is essential for prolonging yeast survival during nutrient deprivation; however, this report shows that some autophagy proteins may also be accelerating population death in those conditions. While leucine starvation caused YCA1-mediated apoptosis characterized by increased annexin V staining, nitrogen deprivation triggered necrotic death characterized by increased propidium iodide uptake. Although a Δatg8 strain died faster than its parental strain during nitrogen starvation, this mutant died slower than its parent during leucine starvation. Conversely, a Δatg11 strain died slower than its parent during nitrogen starvation, but faster during leucine starvation. Curiously, although GFP-Atg8 complemented the Δatg8 mutation, this protein made ATG8 cells more sensitive to nitrogen starvation, and less sensitive to leucine starvation. These results were difficult to explain if autophagy only extended life but could be an indication that a second form of autophagy could concurrently facilitate either apoptotic or necrotic cell death.




BASIC RESEARCH PAPERS

Open Access Article

Dual functions of autophagy in the response of breast tumor cells to radiation: Cytoprotective autophagy with radiation alone and cytotoxic autophagy in radiosensitization by vitamin D₃

Molly L. Bristol, Xu Di, Matthew J. Beckman, Eden N. Wilson, Scott C. Henderson, Aparna Maiti, Zhen Fan and David A. Gewirtz
Pages 739 - 753
http://dx.doi.org/10.4161/auto.19313
Abstract | Full Text | PDF

In MCF-7 breast tumor cells, ionizing radiation promoted autophagy that was cytoprotective; pharmacological or genetic interference with autophagy induced by radiation resulted in growth suppression and/or cell killing (primarily by apoptosis). The hormonally active form of vitamin D, 1,25D₃, also promoted autophagy in irradiated MCF-7 cells, sensitized the cells to radiation and suppressed the proliferative recovery that occurs after radiation alone. 1,25D₃ enhanced radiosensitivity and promoted autophagy in MCF-7 cells that overexpress Her-2/neu as well as in p53 mutant Hs578t breast tumor cells. In contrast, 1,25D₃ failed to alter radiosensitivity or promote autophagy in the BT474 breast tumor cell line with low-level expression of the vitamin D receptor. Enhancement of MCF-7 cell sensitivity to radiation by 1,25D₃ was not attenuated by a genetic block to autophagy due largely to the promotion of apoptosis via the collateral suppression of protective autophagy. However, MCF-7 cells were protected from the combination of 1,25D₃ with radiation using a concentration of chloroquine that produced minimal sensitization to radiation alone. The current studies are consistent with the premise that while autophagy mediates a cytoprotective function in irradiated breast tumor cells, promotion of autophagy can also confer radiosensitivity by vitamin D (1,25D₃). As both cytoprotective and cytotoxic autophagy can apparently be expressed in the same experimental system in response to radiation, this type of model could be utilized to distinguish biochemical, molecular and/or functional differences in these dual functions of autophagy.

Open Access Article

Alpha-synuclein aggregation involves a bafilomycin A₁-sensitive autophagy pathway

Jochen Klucken, Anne-Maria Poehler, Darius Ebrahimi-Fakhari, Jacqueline Schneider, Silke Nuber, Edward Rockenstein, Ursula Schlötzer-Schrehardt, Bradley T. Hyman, Pamela J. McLean, Eliezer Masliah and Juergen Winkler
Pages 754 - 766
http://dx.doi.org/10.4161/auto.19371
Abstract | Full Text | PDF

Synucleinopathies like Parkinson disease and dementia with Lewy bodies (DLB) are characterized by α-synuclein aggregates within neurons (Lewy bodies) and their processes (Lewy neurites). Whereas α-synuclein has been genetically linked to the disease process, the pathological relevance of α-synuclein aggregates is still debated. Impaired degradation is considered to result in aggregation of α-synuclein. In addition to the ubiquitin-proteasome degradation, the autophagy-lysosomal pathway (ALP) is involved in intracellular degradation processes for α-synuclein. Here, we asked if modulation of ALP affects α-synuclein aggregation and toxicity. We have identified an induction of the ALP markers LAMP-2A and LC3-II in human brain tissue from DLB patients, in a transgenic mouse model of synucleinopathy, and in a cell culture model for α-synuclein aggregation. ALP inhibition using bafilomycin A₁ (BafA1) significantly potentiates toxicity of aggregated α-synuclein species in transgenic mice and in cell culture. Surprisingly, increased toxicity is paralleled by reduced aggregation in both in vivo and in vitro models. The dichotomy of effects on aggregating and nonaggregating species of α-synuclein was specifically sensitive to BafA1 and could not be reproduced by other ALP inhibitors. The present study expands on the accumulating evidence regarding the function of ALP for α-synuclein degradation by isolating an aggregation specific, BafA1-sensitive, ALP-related pathway. Our data also suggest that protein aggregation may represent a detoxifying event rather than being causal for cellular toxicity.

Open Access Article

The deubiquitinating enzyme USP36 controls selective autophagy activation by ubiquitinated proteins

Emmanuel Taillebourg, Isabel Gregoire, Perrine Viargues, Anne-Claire Jacomin, Dominique Thevenon, Mathias Faure and Marie-Odile Fauvarque
Pages 767 - 779
http://dx.doi.org/10.4161/auto.19381
Abstract | Full Text | PDF

Initially described as a nonspecific degradation process induced upon starvation, autophagy is now known also to be involved in the degradation of specific ubiquitinated substrates such as mitochondria, bacteria and aggregated proteins, ensuring crucial functions in cell physiology and immunity. We report here that the deubiquitinating enzyme USP36 controls selective autophagy activation in Drosophila and in human cells. We show that dUsp36 loss of function autonomously inhibits cell growth while activating autophagy. Despite the phenotypic similarity, dUSP36 is not part of the TOR signaling pathway. Autophagy induced by dUsp36 loss of function depends on p62/SQSTM1, an adaptor for delivering cargo marked by polyubiquitin to autophagosomes. Consistent with p62 requirement, dUsp36 mutant cells display nuclear aggregates of ubiquitinated proteins, including Histone H2B, and cytoplasmic ubiquitinated proteins; the latter are eliminated by autophagy. Importantly, USP36 function in p62-dependent selective autophagy is conserved in human cells. Our work identifies a novel, crucial role for a deubiquitinating enzyme in selective autophagy.

Open Access Article

A role for Atg8–PE deconjugation in autophagosome biogenesis

Usha Nair, Wei-Lien Yen, Muriel Mari, Yang Cao, Zhiping Xie, Misuzu Baba, Fulvio Reggiori and Daniel J. Klionsky
Pages 780 - 793
http://dx.doi.org/10.4161/auto.19385
Abstract | Full Text | PDF

Formation of the autophagosome is likely the most complex step of macroautophagy, and indeed it is the morphological and functional hallmark of this process; accordingly, it is critical to understand the corresponding molecular mechanism. Atg8 is the only known autophagy-related (Atg) protein required for autophagosome formation that remains associated with the completed sequestering vesicle. Approximately one-fourth of all of the characterized Atg proteins that participate in autophagosome biogenesis affect Atg8, regulating its conjugation to phosphatidylethanolamine (PE), localization to the phagophore assembly site and/or subsequent deconjugation. An unanswered question in the field regards the physiological role of the deconjugation of Atg8–PE. Using an Atg8 mutant that bypasses the initial Atg4-dependent processing, we demonstrate that Atg8 deconjugation is an important step required to facilitate multiple events during macroautophagy. The inability to deconjugate Atg8–PE results in the mislocalization of this protein to the vacuolar membrane. We also show that the deconjugation of Atg8–PE is required for efficient autophagosome biogenesis, the assembly of Atg9-containing tubulovesicular clusters into phagophores/autophagosomes, and for the disassembly of PAS-associated Atg components.

Open Access Article

Internalized gap junctions are degraded by autophagy

John T. Fong, Rachael M. Kells, Anna M. Gumpert, Jutta Y. Marzillier, Michael W. Davidson and Matthias M. Falk
Pages 794 - 811
http://dx.doi.org/10.4161/auto.19390
Abstract | Full Text | PDF

Direct intercellular communication mediated by gap junctions (GJs) is a hallmark of normal cell and tissue physiology. In addition, GJs significantly contribute to physical cell-cell adhesion. Clearly, these cellular functions require precise modulation. Typically, GJs represent arrays of hundreds to thousands of densely packed channels, each one assembled from two half-channels (connexons), that dock head-on in the extracellular space to form the channel arrays that link neighboring cells together. Interestingly, docked GJ channels cannot be separated into connexons under physiological conditions, posing potential challenges to GJ channel renewal and physical cell-cell separation. We described previously that cells continuously—and effectively after treatment with natural inflammatory mediators—internalize their GJs in an endo-/exocytosis process that utilizes clathrin-mediated endocytosis components, thus enabling these critical cellular functions. GJ internalization generates characteristic cytoplasmic double-membrane vesicles, described and termed earlier annular GJs (AGJs) or connexosomes. Here, using expression of the major fluorescent-tagged GJ protein, connexin 43 (Cx43-GFP/YFP/mApple) in HeLa cells, analysis of endogenously expressed Cx43, ultrastructural analyses, confocal colocalization microscopy, pharmacological and molecular biological RNAi approaches depleting cells of key-autophagic proteins, we provide compelling evidence that GJs, following internalization, are degraded by autophagy. The ubiquitin-binding protein p62/sequestosome 1 was identified in targeting internalized GJs to autophagic degradation. While previous studies identified proteasomal and endo-/lysosomal pathways in Cx43 and GJ degradation, our study provides novel molecular and mechanistic insights into an alternative GJ degradation pathway. Its recent link to health and disease lends additional importance to this GJ degradation mechanism and to autophagy in general.

Open Access Article

Curcumin induces autophagy to protect vascular endothelial cell survival from oxidative stress damage

Jing Han, Xue-Yang Pan, Yan Xu, Yuan Xiao, Yu An, Lu Tie, Yan Pan and Xue-Jun Li
Pages 812 - 825
http://dx.doi.org/10.4161/auto.19471
Abstract | Full Text | PDF

Our study first proposed that curcumin could protect human endothelial cells from the damage caused by oxidative stress via autophagy. Furthermore, our results revealed that curcumin causes some novel cellular mechanisms that promote autophagy as a protective effect. Pretreatment with curcumin remarkably improves the survival of human umbilical vein endothelial cells (HUVECs) from H₂O₂-induced viability loss, which specifically evokes an autophagic response. Exposed to H₂O₂, curcumin-treated HUVECs upregulate the level of microtubule-associated protein 1 light chain 3-II (LC3-II), the number of autophagosomes, and the degradation of p62. We show that this compound promotes BECN1 expression and inhibits the phosphatidylinositol 3-kinase (PtdIns3K)-AKT-mechanistic target of rapamycin (MTOR) signaling pathway. Curcumin can also reverse FOXO1 (a mediator of autophagy) nuclear localization along with causing an elevated level of cytoplasmic acetylation of FOXO1 and the interaction of acetylated FOXO1 and ATG7, under the circumstance of oxidative stress. Additionally, knockdown of FOXO1 by shRNA inhibits not only the protective effects that curcumin induced, but the autophagic process, from the quantity of LC3-II to the expression of RAB7. These results suggest that curcumin induces autophagy, indicating that curcumin has the potential for use as an autophagic-related antioxidant for prevention and treatment of oxidative stress. These data uncover a brand new protective mechanism involving FOXO1 as having a critical role in regulating autophagy in HUVECs, and suggest a novel role for curcumin in inducing a beneficial form of autophagy in HUVECs, which may be a potential multitargeted therapeutic avenue for the treatment of oxidative stress-related cardiovascular diseases.




TRANSLATIONAL RESEARCH PAPER

Open Access Article

Autophagy plays a critical role in kidney tubule maintenance, aging and ischemia-reperfusion injury

Shuya Liu, Björn Hartleben, Oliver Kretz, Thorsten Wiech, Peter Igarashi, Noboru Mizushima, Gerd Walz and Tobias B. Huber
Pages 826 - 837
http://dx.doi.org/10.4161/auto.19419
Abstract | Full Text | PDF

Autophagy is responsible for the degradation of protein aggregates and damaged organelles. Several studies have reported increased autophagic activity in tubular cells after kidney injury. Here, we examine the role of tubular cell autophagy in vivo under both physiological conditions and stress using two different tubular-specific Atg5-knockout mouse models. While Atg5 deletion in distal tubule cells does not cause a significant alteration in kidney function, deleting Atg5 in both distal and proximal tubule cells results in impaired kidney function. Already under physiological conditions, Atg5-null tubule cells display a significant accumulation of p62 and oxidative stress markers. Strikingly, tubular cell Atg5-deficiency dramatically sensitizes the kidneys to ischemic injury, resulting in impaired kidney function, accumulation of damaged mitochondria as well as increased tubular cell apoptosis and proliferation, highlighting the critical role that autophagy plays in maintaining tubular cell integrity during stress conditions.




AUTOPHAGIC PUNCTA

Open Access Article

Selective autophagy in the aid of plant germination and response to nutrient starvation

Arik Honig, Tamar Avin-Wittenberg and Gad Galili
Pages 838 - 839
http://dx.doi.org/10.4161/auto.19666
Abstract | Full Text | PDF

Selective autophagy, mediated by Atg8 binding proteins, has not been extensively studied in plants. Plants possess a large gene family encoding multiple isoforms of the Atg8 protein. We have recently reported the identification of two new, closely homologous Arabidopsis thaliana plant proteins that bind the Arabidopsis Atg8f protein isoform. These two proteins are specific to plants and have no homologs in nonplant organisms. The expression levels of the genes encoding these proteins are elevated during carbon starvation and also during late stages of seed development. Exposure of young seedlings to carbon starvation induces the production of a newly identified compartment decorated by these Atg8-binding proteins. This compartment dynamically moves along the endoplasmic reticulum membrane and is also finally transported into the vacuole. Enhanced or suppressed expression of these Atg8-binding proteins respectively enhances or suppresses seed germination under suboptimal germination conditions, indicating that they contribute to seed germination vigor.

Open Access Article

A new role for ATM: Regulating mitochondrial function and mitophagy

Yasmine A. Valentin-Vega and Michael B. Kastan
Pages 840 - 841
http://dx.doi.org/10.4161/auto.19693
Abstract | Full Text | PDF

The various pathologies in ataxia telangiectasia (A-T) patients including T-cell lymphomagenesis have been attributed to defects in the DNA damage response pathway because ATM, the gene mutated in this disease, is a key mediator of this process. Analysis of Atm-deficient thymocytes in mice reveals that the absence of this gene results in altered mitochondrial homeostasis, a phenomenon that appears to result from abnormal mitophagy engagement. Interestingly, allelic loss of the autophagic gene Becn1 delays tumorigenesis in Atm-null mice presumably by reversing the mitochondrial abnormalities and not by improving the DNA damage response (DDR) pathway. Thus, ATM plays a critical role in modulating mitochondrial homeostasis perhaps by regulating mitophagy.

Open Access Article

The TP53 tumor suppressor and autophagy in malignant lymphoma

Zijun Y. Xu-Monette and Ken H. Young
Pages 842 - 845
http://dx.doi.org/10.4161/auto.19703
Abstract | Full Text | PDF

The TP53 (p53) protein is a well-known tumor suppressor that plays a crucial role in maintaining genome stability under various cellular stresses. Loss of TP53 causes lymphomagenesis in mouse models and/or promotes tumor progression. However, the prognostic significance of TP53 has been inconsistent in human cancers including malignant lymphoma. In our recent review of TP53 dysfunction in lymphoid malignancies, we discussed the fact that the TP53 function in autophagy may be one of the important mechanisms responsible for the inconsistency of TP53 prognostic value, in that autophagy can promote survival of lymphoma cells by recycling toxic intracellular materials and inhibiting apoptosis. Here we discuss the biological mechanisms of TP53 functional switches from apoptosis to autophagy, and provide a brief summary of how TP53 regulates autophagy through its transcriptional activity on 14 genes of the TP53 pathway.

Open Access Article

Direct molecular interactions between HMGB1 and TP53 in colorectal cancer

Kristen M. Livesey, Rui Kang, Herbert J. Zeh, III, Michael T. Lotze and Daolin Tang
Pages 846 - 848
http://dx.doi.org/10.4161/auto.19891
Abstract | Full Text | PDF

Tumorigenesis and the efficacy of cancer therapeutics are both defined by the balance between autophagy and apoptosis. High-mobility group box 1 (HMGB1) is a DNA chaperone and extracellular damage-associated molecular pattern molecule (DAMP) with pro-autophagic activity. TP53/p53 plays a transcription-dependent and -independent role in the regulation of apoptosis, autophagy, metabolism, cell cycle progression, and many other processes. Both HMGB1 and TP53 are tightly linked with the development of cancer, associated with many of the hallmarks defining the altered biology of cancer. We have demonstrated that TP53-HMGB1 complexes regulate the balance between apoptosis and autophagy through regulation of the cytosolic localization of the reciprocal binding partner, whereby increased cytosolic HMGB1 enhances autophagy and increased cytosolic TP53 enhances apoptosis in colon cancer cells. We found that HMGB1-mediated autophagy promotes cell survival in TP53-dependent processes, and that TP53 inhibits autophagy through negative regulation of HMGB1-BECN1 complexes. Nuclear localization of TP53 and HMGB1 in tumors from patients with colon adenocarcinoma had a positive trend with survival time from diagnosis. Thus, HMGB1 and TP53 are critical in the crossregulation of apoptosis and autophagy and central to colon cancer biology.

Open Access Article

Autophagy fuels tissue fibrogenesis

Virginia Hernández-Gea and Scott L. Friedman
Pages 849 - 850
http://dx.doi.org/10.4161/auto.19947
Abstract | Full Text | PDF

Activation of hepatic stellate cells (HSC), a resident pericytic cell in liver, into a proliferative and fibrogenic cell type, is the principal event underlying hepatic fibrosis following injury. Release of lipid droplets (LD) containing retinyl esters and triglyceride is a defining feature of HSC activation, yet the basis for this release has remained mysterious. Here we offer a surprising discovery that autophagy is the missing link underlying LD release, by stimulating metabolism of their contents to provide the energy vital to fuel HSC activation. By specifically inhibiting the autophagic pathway in activated HSC, LD release is impaired and cellular ATP levels are decreased. Moreover, animals with HSC-specific deletion of Atg7 display attenuated activation following liver injury, leading to reduced fibrosis in vivo. We further demonstrate that fibrogenic cells from other organs, including kidney and lung, also rely on autophagy as a core pathway driving the scarring response. Our results provide a novel framework for understanding pathways underlying fibrogenic cell responses to tissue injury.

Open Access Article

DISC1 and the aggresome: A disruption to cellular function?

Talia Atkin and Josef Kittler
Pages 851 - 852
http://dx.doi.org/10.4161/auto.19979
Abstract | Full Text | PDF

Disrupted in Schizophrenia 1 (DISC1) is a key susceptibility gene for major psychiatric disorders. DISC1 plays a role in key neuronal processes such as neuronal proliferation, migration, integration and function via DISC1's roles at the centrosome and synapse, and in the regulation of intracellular signaling pathways. Recently, the idea of protein aggregation as a disease mechanism for DISC1 has been suggested. In our recent paper we explore these DISC1 protein aggregates in cell lines and neurons and find they are recruited to the aggresome and cause disruption of DISC1 function in intracellular transport.

Open Access Article

microRNA 30A promotes autophagy in response to cancer therapy

Yan Yu, Lizhi Cao, Liangchun Yang, Rui Kang, Michael Lotze and Daolin Tang
Pages 853 - 855
http://dx.doi.org/10.4161/auto.20053
Abstract | Full Text | PDF

microRNAs (miRNAs) are a class of small regulatory RNAs that regulate gene expression at the post-transcriptional level. miRNAs play important roles in the regulation of development, growth, and metastasis of cancer, and in determining the response of tumor cells to anticancer therapy. In recent years, they have also emerged as important regulators of autophagy, a lysosomal-mediated pathway that contributes to degradation of a cell's own components. Imatinib, a targeted competitive inhibitor of the BCR-ABL1 tyrosine kinase, has revolutionized the clinical treatment of chronic myelogenous leukemia (CML). We demonstrate that MIR30A-mediated autophagy enhances imatinib resistance against CML including primary stem and progenitor cells. MIR30A, but not MIR101, is a potent inhibitor of autophagy by selectively downregulating BECN1 and ATG5 expression in CML cells. MIR30A mimics, as well as knockdown of BECN1 and ATG5, increases intrinsic apoptotic pathways. In contrast, the antagomir-30A increases autophagy and inhibits intrinsic apoptotic pathways, confirming that autophagy serves to protect against apoptosis. Taken together, these data clarify some of the underlying molecular mechanisms of tyrosine kinase inhibitor-induced autophagy.

Open Access Article

BCL2-CISD2: An ER complex at the nexus of autophagy and calcium homeostasis?

Natasha C. Chang, Mai Nguyen and Gordon C. Shore
Pages 856 - 857
http://dx.doi.org/10.4161/auto.20054
Abstract | Full Text | PDF

CISD2, an ER BCL2-associated autophagy regulator also known as NAF-1, is responsible for the human degenerative disorder Wolfram Syndrome 2. In order to interrogate the physiological role of CISD2 we generated and characterized the Cisd2 gene deletion in mice. Cisd2 null mice manifest significant degeneration in skeletal muscle tissues, which is accompanied with augmented autophagy, dysregulated Ca²⁺ homeostasis and elongated mitochondria. Our findings describe a novel role for BCL2-CISD2 in the homeostatic maintenance of skeletal muscle. It remains to be elucidated how and if the antagonism of the BECN1 autophagy-initiating complex and modulation of ER Ca²⁺ homeostasis by BCL2-CISD2 are interconnected.

Open Access Article

Autophagosome assembly and cargo capture in the distal axon

Sandra Maday and Erika L.F. Holzbaur
Pages 858 - 860
http://dx.doi.org/10.4161/auto.20055
Abstract | Full Text | PDF

Autophagy is an essential lysosomal degradation pathway in neurons, yet the basic mechanisms involved are poorly understood. Here, we discuss our recent study in which we define autophagosome dynamics in primary neurons. We find that autophagosomes initiate at the distal tip of the axon in primary neurons and undergo retrograde transport toward the cell soma. As they move distally to proximally along the axon, autophagosomes mature and become increasingly acidified, consistent with the formation of an autolysosomal compartment that may more effectively catalyze the degradation of enveloped cargo. Our findings suggest that autophagosome biogenesis and maturation is a constitutive process in primary neurons that is temporally and spatially regulated along the axon.

Open Access Article

The plasma membrane as a control center for autophagy

Kevin Moreau and David C. Rubinsztein
Pages 861 - 863
http://dx.doi.org/10.4161/auto.20060
Abstract | Full Text | PDF

Autophagosomes may derive membrane from diverse sources, including the plasma membrane, Golgi, endoplasmic reticulum and mitochondria. The plasma membrane contributes membrane to ATG12–ATG5-ATG16L1-positive phagophore precursor vesicles (LC3-negative) by both clathrin-dependent and -independent routes. We recently observed that ARF6 regulates autophagy and that this could be explained, at least in part, by its role in the generation of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P₂], which influences endocytic uptake of plasma membrane into autophagosome precursors. The subsequent maturation of these small phagophore precursors into phagophores (ATG12–ATG5-ATG16L1-positive and LC3-positive), is assisted by SNARE-mediated homotypic fusion that increase their size and enhance their ability to acquire LC3-II. It appears that a plasma membrane-derived pool of VAMP7 is a key mediator of these fusion events. Thus, events at the plasma membrane may regulate distinct steps in the biogenesis of phagophores.




ERRATUM

Open Access Article

Erratum to: Lu J-H, Tan J-Q, Durairajan SSK, Liu L-F, Zhang Z-H, Ma L, et al. Isorhynchophylline, a natural alkaloid, promotes the degradation of α-synuclein in neuronal cells via inducing autophagy. Autophagy 2012; 8:98–108

Jia-Hong Lu, Jie-Qiong Tan, Siva Sundara Kumar Durairajan, Liang-Feng Liu, Zhuo-Hua Zhang, Long Ma, Han-Ming Shen, H.Y. Edwin Chan and Min Li
Pages 864 - 866
http://dx.doi.org/10.4161/auto.20350
Full Text | PDF