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【聚焦】走进细胞自噬 [精华]

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tangdl2000

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Proc Natl Acad Sci U S A. 2011 Apr 25. [Epub ahead of print]

Autophagosome targeting and membrane curvature sensing by Barkor/Atg14(L).
自噬体的定位和膜折叠需要Barkor/Atg14

Fan W, Nassiri A, Zhong Q.
Source
Division of Biochemistry and Molecular Biology, Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.
Abstract
The class III phosphatidylinositol 3-kinase (PI3KC3) is crucial for autophagosome biogenesis. It has been long speculated to nucleate the autophagosome membrane, but the biochemical mechanism of such nucleation activity remains unsolved. We recently identified Barkor/Atg14(L) as the targeting factor for PI3KC3 to autophagosome membrane. Here, we show that we have characterized the region of Barkor/Atg14(L) required for autophagosome targeting and identified the BATS [Barkor/Atg14(L) autophagosome targeting sequence] domain at the carboxyl terminus of Barkor. Bioinformatics and mutagenesis analyses revealed that the BATS domain binds to autophagosome membrane via the hydrophobic surface of an intrinsic amphipathic alpha helix. BATS puncta overlap with Atg16 and LC3, and partially with DFCP1, in a stress-inducible manner. Ectopically expressed BATS accumulates on highly curved tubules that likely represent intermediate autophagic structures. PI3KC3 recruitment and autophagy stimulation by Barkor/Atg14(L) require the BATS domain. Furthermore, our biochemical analyses indicate that the BATS domain directly binds to the membrane, and it favors membrane composed of phosphatidylinositol 3-phosphate [PtdIns(3)P] and phosphatidylinositol 4,5-biphosphate [PtdIns(4,5)P2]. By binding preferentially to curved membranes incorporated with PtdIns(3)P but not PtdIns(4,5)P2, the BATS domain is capable of sensing membrane curvature. Thus, we propose a novel model of PI3KC3 autophagosome membrane nucleation in which its autophagosome-specific adaptor, Barkor, accumulates on highly curved PtdIns(3)P enriched autophagic membrane via its BATS domain to sense and maintain membrane curvature.

PMID: 21518905 [PubMed - as supplied by publisher]

1016472108.full.pdf(1416.56k)

2011-05-10 22:31

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tangdl2000

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J Biol Chem. 2011 May 2. [Epub ahead of print]

Dynamics of the degradation of ubiquitinated proteins by proteasomes and autophagy: its association with sequestosome 1/P62.
通过泛素蛋白酶体和自噬降解蛋白的动力学以及与sequestosome1/P62的协同作用

Myeku N, Figueiredo-Pereira ME.
Source
Hunter College, City University of New York, United States;
Abstract
Proteotoxicity resulting from accumulation of damaged/unwanted proteins contributes prominently to cellular aging and neurodegeneration. Proteasomal removal of these proteins upon covalent polyubiquitination is highly regulated. Recent reports proposed a role for autophagy in clearance of diffuse ubiquitinated proteins delivered by p62/sqstm1. Here, we compared the turnover dynamics of endogenous ubiquitinated proteins by proteasomes and autophagy by assessing the effect of their inhibitors. Autophagy inhibitors bafilomycin A1, ammonium chloride and 3-methyladenine failed to increase ubiquitinated protein levels. The proteasome inhibitor epoxomicin raised ubiquitinated protein levels at least three-fold higher than the lysosomotropic agent chloroquine. These trends were observed in SK-N-SH cells under serum or serum-free conditions and in WT or Atg5-/- mouse embryonic fibroblasts (MEFs). Notably, chloroquine considerably inhibited proteasomes in SK-N-SH cells and MEFs. In these cells, elevation of p62/sqstm1 was greater upon proteasome inhibition than with all autophagy inhibitors tested, and was reduced in Atg5-/- MEFs. With epoxomicin, soluble p62/sqstm1 associated with proteasomes and p62/sqstm1 aggregates contained inactive proteasomes, ubiquitinated proteins and autophagosomes. Prolonged autophagy inhibition (96 hours) failed to elevate ubiquitinated proteins in rat cortical neurons, while epoxomicin did. Moreover, prolonged autophagy inhibition in cortical neurons markedly increased p62/sqstm1, supporting its degradation mainly by autophagy not proteasomes. In conclusion, we clearly demonstrate that pharmacologic or genetic inhibition of autophagy fails to elevate ubiquitinated proteins unless the proteasome is affected. We also provide strong evidence that p62/sqstm1 associates with proteasomes, and that autophagy degrades p62/sqstm1. Overall, the function of p62/sqstm1 in the proteasomal pathway and autophagy requires further elucidation.

PMID: 21536669 [PubMed - as supplied by publisher] Free Article

jbc.M110.149252.full.pdf(1826.46k)

2011-05-10 23:01

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tangdl2000

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Mol Biol Cell. 2011 Apr 27. [Epub ahead of print]

The LC3 recruitment mechanism is separate from Atg9L1-dependent membrane formation in the autophagic response against Salmonella.
LC3的招募机制是不同与Atg9L1依赖性自噬膜的形成机制

Kageyama S, Omori H, Saitoh T, Sone T, Guan JL, Akira S, Imamoto F, Noda T, Yoshimori T.
Source
*Department of Genetics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan ?Laboratory of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan ?Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan §Laboratory of Host Defense, WPI Immunology Frontier Research Center (IFReC), Integrated Life Science Building, Osaka University 3-1 Yamadaoka, Suita, 565-0871, Osaka, Japan ‖Department of Host Defense, Research Institute for Microbial Diseases, Integrated Life Science Building, Osaka University 3-1 Yamadaoka, Suita, 565-0871, Osaka, Japan ?Department of Molecular Biology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan #Department of Internal Medicine-MMG, University of Michigan Medical School, Ann Arbor, MI 48109.
Abstract
Salmonella develops into resident bacteria in epithelial cells, and the autophagic machinery (Atg) is thought to play an important role in this process. Here we show that an autophagosome-like double membrane structure surrounds the Salmonella still residing within the Salmonella-containing vacuole (SCV). This double membrane is defective in Atg9L1- and FIP200-deficient cells. Atg9L1 and FIP200 are important for autophagy-specific recruitment of the PI3-kinase complex. However, in the absence of Atg9L1, FIP200, and the PI3-kinase complex, LC3 and its E3-like enzyme, the Atg16L complex, are still recruited to Salmonella. We propose that the LC3 system is recruited through a mechanism that is independent of isolation membrane generation.

PMID: 21525242 [PubMed - as supplied by publisher] Free Article

mbc.E10-11-0893v1.pdf(1901.68k)

2011-05-10 23:31

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• 丁香早知道 - 12.6 | 没考研的“差生”同学年薪百万，而我还为生存挣扎

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tangdl2000

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Science. 2011 Apr 21. [Epub ahead of print]
Spatial Coupling of mTOR and Autophagy Augments Secretory Phenotypes.
空间耦合mTOR和自噬增大分泌表型

Narita M, Young AR, Arakawa S, Samarajiwa SA, Nakashima T, Yoshida S, Hong S, Berry LS, Reichelt S, Ferreira M, Tavaré S, Inoki K, Shimizu S, Narita M.
Source
Cancer Research UK Cambridge Research Institute (CRI), Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK.
Abstract
Protein synthesis and autophagic degradation are regulated in an opposite manner by mammalian target of rapamycin (mTOR), whereas under certain conditions it would be beneficial if they occurred in unison to handle rapid protein turnover. We observed a distinct cellular compartment at the trans-side of the Golgi apparatus, the "TOR-autophagy spatial coupling compartment" (TASCC), where (auto)lysosomes and mTOR accumulated during Ras-induced senescence. mTOR recruitment to the TASCC was amino acid- and Rag guanosine triphosphatase (GTPase)-dependent, and disruption of mTOR localization to the TASCC suppressed interleukin-6/8 synthesis. TASCC-formation was observed during macrophage differentiation and in glomerular podocytes; both displayed increased protein secretion. The spatial coupling of cells' catabolic and anabolic machinery could augment their respective functions and facilitate the mass synthesis of secretory proteins.

PMID: 21512002 [PubMed - as supplied by publisher]

Science-2011-Narita-science.1205407.pdf(1756.04k)

2011-05-11 00:05

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• 丁香热议——谈恋爱遇见住院总：短信不回，电话不接，还以为ta出轨了！

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