Publication Date:
2011-10-25
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229641/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229641/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Orvedahl, Anthony -- Sumpter, Rhea Jr -- Xiao, Guanghua -- Ng, Aylwin -- Zou, Zhongju -- Tang, Yi -- Narimatsu, Masahiro -- Gilpin, Christopher -- Sun, Qihua -- Roth, Michael -- Forst, Christian V -- Wrana, Jeffrey L -- Zhang, Ying E -- Luby-Phelps, Katherine -- Xavier, Ramnik J -- Xie, Yang -- Levine, Beth -- AI062773/AI/NIAID NIH HHS/ -- AI109617/AI/NIAID NIH HHS/ -- CA84254/CA/NCI NIH HHS/ -- DK043351/DK/NIDDK NIH HHS/ -- DK086502/DK/NIDDK NIH HHS/ -- DK83756/DK/NIDDK NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK040561-15/DK/NIDDK NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 AI051367/AI/NIAID NIH HHS/ -- R01 AI051367-06/AI/NIAID NIH HHS/ -- UL1 RR024982/RR/NCRR NIH HHS/ -- ZIA BC011168-03/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Dec 1;480(7375):113-7. doi: 10.1038/nature10546.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9113, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22020285" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Autophagy/*genetics
;
Capsid Proteins/metabolism
;
*Genome-Wide Association Study
;
HeLa Cells
;
Humans
;
Lysosomes/metabolism
;
Mice
;
Mitochondria/metabolism
;
Protein Transport/genetics
;
RNA, Small Interfering/*genetics
;
Sindbis Virus/metabolism
;
Ubiquitin-Protein Ligases/deficiency/genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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