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【聚焦】走进细胞自噬 [精华]

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xiarihuaerzi

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强大~~牛人一个~~敬佩之情何以言表啊~~~

2011-10-26 16:06

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• 【难忘病例】拍胸片发现病人没有心脏？等弄明白结果也还是惊了

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tangdl2000

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Nature. 2011 Oct 23. doi: 10.1038/nature10546. [Epub ahead of print]

Image-based genome-wide siRNA screen identifies selective autophagy factors.
基于图像的基因组siRNA筛选鉴定选择性自噬因子

Orvedahl A, Jr RS, Xiao G, Ng A, Zou Z, Tang Y, Narimatsu M, Gilpin C, Sun Q, Roth M, Forst CV, Wrana JL, Zhang YE, Luby-Phelps K, Xavier RJ, Xie Y, Levine B.
Source1] Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9113, USA [2] Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9113, USA [3].

Abstract
Selective autophagy involves the recognition and targeting of specific cargo, such as damaged organelles, misfolded proteins, or invading pathogens for lysosomal destruction. Yeast genetic screens have identified proteins required for different forms of selective autophagy, including cytoplasm-to-vacuole targeting, pexophagy and mitophagy, and mammalian genetic screens have identified proteins required for autophagy regulation. However, there have been no systematic approaches to identify molecular determinants of selective autophagy in mammalian cells. Here, to identify mammalian genes required for selective autophagy, we performed a high-content, image-based, genome-wide small interfering RNA screen to detect genes required for the colocalization of Sindbis virus capsid protein with autophagolysosomes. We identified 141 candidate genes required for viral autophagy, which were enriched for cellular pathways related to messenger RNA processing, interferon signalling, vesicle trafficking, cytoskeletal motor function and metabolism. Ninety-six of these genes were also required for Parkin-mediated mitophagy, indicating that common molecular determinants may be involved in autophagic targeting of viral nucleocapsids and autophagic targeting of damaged mitochondria. Murine embryonic fibroblasts lacking one of these gene products, the C2-domain containing protein, SMURF1, are deficient in the autophagosomal targeting of Sindbis and herpes simplex viruses and in the clearance of damaged mitochondria. Moreover, SMURF1-deficient mice accumulate damaged mitochondria in the heart, brain and liver. Thus, our study identifies candidate determinants of selective autophagy, and defines SMURF1 as a newly recognized mediator of both viral autophagy and mitophagy.

PMID: 22020285

nature10546.pdf(1652.74k)

2011-10-27 03:14

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• 【备考】考博联系导师邮件模板（含专家推荐信和读博计划书）

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tangdl2000

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Mol Cell. 2011 Oct 21;44(2):304-16.
DEPTOR, an mTOR Inhibitor, Is a Physiological Substrate of SCF(βTrCP) E3 Ubiquitin Ligase and Regulates Survival and Autophagy.
DEPTOR作为mtor抑制剂调节存活和自噬

Zhao Y, Xiong X, Sun Y.
SourceDivision of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, 4424B MS-1, 1301 Catherine Street, Ann Arbor, MI 48109, USA.

Abstract
DEPTOR, an inhibitor of mTORC1 and mTORC2, is degraded via ubiquitin-proteasome pathway by an unknown E3 ubiquitin ligase. Here we report that DEPTOR is a physiological substrate of SCF(βTrCP) E3 ligase for targeted degradation. Upon growth factor stimulation, RSK1 and S6K1 kinases are activated to phosphorylate DEPTOR, which is then recognized by the F box protein, βTrCP, via its degron sequence for subsequent ubiquitination and degradation by SCF E3. Endogenous DEPTOR levels are negatively regulated by βTrCP. DEPTOR half-life is shortened by βTrCP but extended by a dominant-negative mutant of βTrCP, by RSK1/S6K1 inhibition, and by βTrCP degron site mutations. Biologically, DEPTOR accumulation upon βTrCP knockdown inactivates mTORC1 and activates AKT in cancer cells to confer resistance to rapamycin and paclitaxel. Furthermore, DEPTOR accumulates upon glucose deprivation and mTOR inhibition to induce autophagy. Thus, βTrCP-DEPTOR-mTOR intertwine to regulate cell survival and autophagy.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID: 22017876 [PubMed - in process]

science.pdf(2014.72k)

2011-10-27 03:17

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• 2019 年度丁香十佳病例入围榜单出炉！你的病例上榜了吗？

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tangdl2000

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Mol Cell. 2011 Oct 21;44(2):279-89.
Serine 403 Phosphorylation of p62/SQSTM1 Regulates Selective Autophagic Clearance of Ubiquitinated Proteins.
p62/SQSTM1磷酸化调节选择性范素华降解

Matsumoto G, Wada K, Okuno M, Kurosawa M, Nukina N.
SourceLaboratory for Structural Neuropathology, RIKEN Brain Science Institute and CREST/JST, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.

Abstract
Selective macroautophagy (autophagy) of ubiquitinated protein is implicated as a compensatory mechanism of the ubiquitin-proteasome system. p62/SQSTM1 is a key molecule managing autophagic clearance of polyubiquitinated proteins. However, little is known about mechanisms controlling autophagic degradation of polyubiquitinated proteins. Here, we show that the specific phosphorylation of p62 at serine 403 (S403) in its ubiquitin-associated (UBA) domain increases the affinity between UBA and polyubiquitin chain, resulting in efficiently targeting polyubiquitinated proteins in "sequestosomes" and stabilizing sequestosome structure as a cargo of ubiquitinated proteins for autophagosome entry. Casein kinase 2 (CK2) phosphorylates S403 of p62 directly. Furthermore, CK2 overexpression or phosphatase inhibition reduces the formation of inclusion bodies of the polyglutamine-expanded huntingtin exon1 fragment in a p62-dependent manner. We propose that phosphorylation of p62 at S403 regulates autophagic clearance of ubiquitinated proteins and protein aggregates that are poorly degraded by proteasomes.

Copyright © 2011 Elsevier Inc. All rights reserved.

PMID: 22017874

science.pdf(1696.17k)

2011-10-27 03:23

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• 丁香早知道 - 12.4 | 被老外吹爆的避孕方法，为何中国女性不敢用？

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