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PMID:23455425

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Citation

Hamasaki, M, Furuta, N, Matsuda, A, Nezu, A, Yamamoto, A, Fujita, N, Oomori, H, Noda, T, Haraguchi, T, Hiraoka, Y, Amano, A and Yoshimori, T (2013) Autophagosomes form at ER-mitochondria contact sites. Nature 495:389-93

Abstract

Autophagy is a tightly regulated intracellular bulk degradation/recycling system that has fundamental roles in cellular homeostasis. Autophagy is initiated by isolation membranes, which form and elongate as they engulf portions of the cytoplasm and organelles. Eventually isolation membranes close to form double membrane-bound autophagosomes and fuse with lysosomes to degrade their contents. The physiological role of autophagy has been determined since its discovery, but the origin of autophagosomal membranes has remained unclear. At present, there is much controversy about the organelle from which the membranes originate--the endoplasmic reticulum (ER), mitochondria and plasma membrane. Here we show that autophagosomes form at the ER-mitochondria contact site in mammalian cells. Imaging data reveal that the pre-autophagosome/autophagosome marker ATG14 (also known as ATG14L) relocalizes to the ER-mitochondria contact site after starvation, and the autophagosome-formation marker ATG5 also localizes at the site until formation is complete. Subcellular fractionation showed that ATG14 co-fractionates in the mitochondria-associated ER membrane fraction under starvation conditions. Disruption of the ER-mitochondria contact site prevents the formation of ATG14 puncta. The ER-resident SNARE protein syntaxin 17 (STX17) binds ATG14 and recruits it to the ER-mitochondria contact site. These results provide new insight into organelle biogenesis by demonstrating that the ER-mitochondria contact site is important in autophagosome formation.

Links

PubMed Online version:10.1038/nature11910

Keywords

Adaptor Proteins, Vesicular Transport/metabolism; Animals; Autophagy; COS Cells; Cercopithecus aethiops; Endoplasmic Reticulum/metabolism; Endoplasmic Reticulum/ultrastructure; Gene Knockdown Techniques; HEK293 Cells; HeLa Cells; Humans; Intracellular Membranes/metabolism; Mitochondria/metabolism; Mitochondria/ultrastructure; Phagosomes/metabolism; Phagosomes/ultrastructure; Protein Transport; Qa-SNARE Proteins/genetics; Qa-SNARE Proteins/metabolism

Significance

Annotations

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

HUMAN:ACSL4

located_in

GO:0044233: mitochondria-associated endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:MFN2

acts_upstream_of_or_within

GO:0034497: protein localization to phagophore assembly site

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:CALX

located_in

GO:0044233: mitochondria-associated endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:STX17

located_in

GO:0044233: mitochondria-associated endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:STX17

acts_upstream_of_or_within

GO:0034497: protein localization to phagophore assembly site

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:TOM20

located_in

GO:0044233: mitochondria-associated endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ZFYV1

located_in

GO:0000407: phagophore assembly site

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q9HBF4

C

Seeded From UniProt

complete

HUMAN:PACS2

acts_upstream_of_or_within

GO:0000045: autophagosome assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PACS2

acts_upstream_of_or_within

GO:0034497: protein localization to phagophore assembly site

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BAKOR

located_in

GO:0044233: mitochondria-associated endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ATG5

located_in

GO:0044233: mitochondria-associated endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ATG5

located_in

GO:0034045: phagophore assembly site membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ZFYV1

located_in

GO:0000407: phagophore assembly site

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:ZFYV1

located_in

GO:0044233: mitochondria-associated endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:BAKOR

part_of

GO:0044233: mitochondria-associated endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:CALX

part_of

GO:0044233: mitochondria-associated endoplasmic reticulum membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:PACS2

involved_in

GO:0034497: protein localization to phagophore assembly site

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PACS2

involved_in

GO:0000045: autophagosome assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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