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PMID:22020285

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Citation

Orvedahl, A, Sumpter, R Jr, 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 and Levine, B (2011) Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480:113-7

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.

Links

PubMed PMC3229641 Online version:10.1038/nature10546

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; Ubiquitin-Protein Ligases/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:SMUF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P03316

F

Seeded From UniProt

complete

MOUSE:SMUF1

involved_in

GO:0061734: parkin-mediated stimulation of mitophagy in response to mitochondrial depolarization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMUF1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P03316

F

Seeded From UniProt

complete

HUMAN:SMUF1

involved_in

GO:0061753: substrate localization to autophagosome

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMUF1

involved_in

GO:0061736: engulfment of target by autophagosome

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMUF1

involved_in

GO:0071211: protein targeting to vacuole involved in autophagy

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P03316)

Seeded From UniProt

complete

SINDV:POLS

enables

GO:0044389: ubiquitin-like protein ligase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9HCE7

F

Seeded From UniProt

complete

SINDV:POLS

enables

GO:0044389: ubiquitin-like protein ligase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9CUN6

F

Seeded From UniProt

complete

HUMAN:SMUF1

enables

GO:0005543: phospholipid binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:SMUF1

involved_in

GO:0072659: protein localization to plasma membrane

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SMUF1

colocalizes_with

GO:0005739: mitochondrion

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q9CUN6

C

Seeded From UniProt

complete

HUMAN:SMUF1

involved_in

GO:0071211: protein targeting to vacuole involved in autophagy

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_input:(UniProtKB:P03316)

Seeded From UniProt

complete

HUMAN:SMUF1

involved_in

GO:0061736: engulfment of target by autophagosome

ECO:0000315: mutant phenotype evidence used in manual assertion

P

occurs_at:(GO:0005739)

Seeded From UniProt

complete

HUMAN:SMUF1

involved_in

GO:0061753: substrate localization to autophagosome

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_target_start_location:(GO:0005739)

Seeded From UniProt

complete

Notes

See also

References

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