| Structural highlights
Function
[ATG8_YEAST] Involved in cytoplasm to vacuole transport (Cvt) vesicles and autophagosomes formation. With ATG4, may mediate the delivery of the vesicles and autophagosomes to the vacuole via the microtubule cytoskeleton. Participates also in membrane fusion events that take place in the early secretory pathway.[1] [2] [3] [4] [5] [6] [7] [8] [9] [ATG32_YEAST] Mitophagy-specific receptor that recruits the autophagic machinery to mitochondria and regulates selective degradation of mitochondria. Mitophagy contributes to regulate mitochondrial quantity and quality by eliminating the mitochondria to a basal level to fulfill cellular energy requirements and preventing excess ROS production. Recruits ATG11 to the surface of mitochondria. Promotes also autophagy-dependent peroxisome degradation.[10] [11] [12] [13] [14] [15] [16] [17] [18]
Publication Abstract from PubMed
Autophagy-related degradation selective for mitochondria (mitophagy) is an evolutionarily conserved process that is thought to be critical for mitochondrial quality and quantity control. In budding yeast, autophagy-related protein 32 (Atg32) is inserted into the outer membrane of mitochondria with its N- and C-terminal domains exposed to the cytosol and mitochondrial intermembrane space, respectively, and plays an essential role in mitophagy. Atg32 interacts with Atg8, a ubiquitin-like protein localized to the autophagosome, and Atg11, a scaffold protein required for selective autophagy-related pathways, although the significance of these interactions remains elusive. In addition, whether Atg32 is the sole protein necessary and sufficient for initiation of autophagosome formation has not been addressed. Here we show that the Atg32 IMS domain is dispensable for mitophagy. Notably, when anchored to peroxisomes, the Atg32 cytosol domain promoted autophagy-dependent peroxisome degradation, suggesting that Atg32 contains a module compatible for other organelle autophagy. X-ray crystallography reveals that the Atg32 Atg8 family-interacting motif peptide binds Atg8 in a conserved manner. Mutations in this binding interface impair association of Atg32 with the free form of Atg8 and mitophagy. Moreover, Atg32 variants, which do not stably interact with Atg11, are strongly defective in mitochondrial degradation. Finally, we demonstrate that Atg32 forms a complex with Atg8 and Atg11 prior to and independent of isolation membrane generation and subsequent autophagosome formation. Taken together, our data implicate Atg32 as a bipartite platform recruiting Atg8 and Atg11 to the mitochondrial surface and forming an initiator complex crucial for mitophagy.
Autophagy-related protein 32 acts as autophagic degron and directly initiates mitophagy.,Kondo-Okamoto N, Noda NN, Suzuki SW, Nakatogawa H, Takahashi I, Matsunami M, Hashimoto A, Inagaki F, Ohsumi Y, Okamoto K J Biol Chem. 2012 Mar 23;287(13):10631-8. Epub 2012 Feb 3. PMID:22308029[19]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Harding TM, Morano KA, Scott SV, Klionsky DJ. Isolation and characterization of yeast mutants in the cytoplasm to vacuole protein targeting pathway. J Cell Biol. 1995 Nov;131(3):591-602. PMID:7593182
- ↑ Lang T, Schaeffeler E, Bernreuther D, Bredschneider M, Wolf DH, Thumm M. Aut2p and Aut7p, two novel microtubule-associated proteins are essential for delivery of autophagic vesicles to the vacuole. EMBO J. 1998 Jul 1;17(13):3597-607. PMID:9649430 doi:10.1093/emboj/17.13.3597
- ↑ Kirisako T, Baba M, Ishihara N, Miyazawa K, Ohsumi M, Yoshimori T, Noda T, Ohsumi Y. Formation process of autophagosome is traced with Apg8/Aut7p in yeast. J Cell Biol. 1999 Oct 18;147(2):435-46. PMID:10525546
- ↑ Huang WP, Scott SV, Kim J, Klionsky DJ. The itinerary of a vesicle component, Aut7p/Cvt5p, terminates in the yeast vacuole via the autophagy/Cvt pathways. J Biol Chem. 2000 Feb 25;275(8):5845-51. PMID:10681575
- ↑ Legesse-Miller A, Sagiv Y, Glozman R, Elazar Z. Aut7p, a soluble autophagic factor, participates in multiple membrane trafficking processes. J Biol Chem. 2000 Oct 20;275(42):32966-73. PMID:10837468 doi:10.1074/jbc.M000917200
- ↑ Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, Ohsumi M, Takao T, Noda T, Ohsumi Y. The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. J Cell Biol. 2000 Oct 16;151(2):263-76. PMID:11038174
- ↑ Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N, Mizushima N, Tanida I, Kominami E, Ohsumi M, Noda T, Ohsumi Y. A ubiquitin-like system mediates protein lipidation. Nature. 2000 Nov 23;408(6811):488-92. PMID:11100732 doi:10.1038/35044114
- ↑ Kim J, Huang WP, Klionsky DJ. Membrane recruitment of Aut7p in the autophagy and cytoplasm to vacuole targeting pathways requires Aut1p, Aut2p, and the autophagy conjugation complex. J Cell Biol. 2001 Jan 8;152(1):51-64. PMID:11149920
- ↑ Okamoto K, Kondo-Okamoto N, Ohsumi Y. A landmark protein essential for mitophagy: Atg32 recruits the autophagic machinery to mitochondria. Autophagy. 2009 Nov;5(8):1203-5. Epub 2009 Nov 13. PMID:19770589
- ↑ Okamoto K, Kondo-Okamoto N, Ohsumi Y. Mitochondria-anchored receptor Atg32 mediates degradation of mitochondria via selective autophagy. Dev Cell. 2009 Jul;17(1):87-97. PMID:19619494 doi:http://dx.doi.org/S1534-5807(09)00254-8
- ↑ Kanki T, Wang K, Cao Y, Baba M, Klionsky DJ. Atg32 is a mitochondrial protein that confers selectivity during mitophagy. Dev Cell. 2009 Jul;17(1):98-109. PMID:19619495 doi:http://dx.doi.org/S1534-5807(09)00255-X
- ↑ Kanki T, Wang K, Baba M, Bartholomew CR, Lynch-Day MA, Du Z, Geng J, Mao K, Yang Z, Yen WL, Klionsky DJ. A genomic screen for yeast mutants defective in selective mitochondria autophagy. Mol Biol Cell. 2009 Nov;20(22):4730-8. Epub 2009 Sep 30. PMID:19793921 doi:http://dx.doi.org/E09-03-0225
- ↑ Mao K, Wang K, Zhao M, Xu T, Klionsky DJ. Two MAPK-signaling pathways are required for mitophagy in Saccharomyces cerevisiae. J Cell Biol. 2011 May 16;193(4):755-67. doi: 10.1083/jcb.201102092. PMID:21576396 doi:http://dx.doi.org/10.1083/jcb.201102092
- ↑ Sampaio-Marques B, Felgueiras C, Silva A, Rodrigues M, Tenreiro S, Franssens V, Reichert AS, Outeiro TF, Winderickx J, Ludovico P. SNCA (alpha-synuclein)-induced toxicity in yeast cells is dependent on sirtuin 2 (Sir2)-mediated mitophagy. Autophagy. 2012 Oct;8(10):1494-509. doi: 10.4161/auto.21275. Epub 2012 Aug 23. PMID:22914317 doi:http://dx.doi.org/10.4161/auto.21275
- ↑ Motley AM, Nuttall JM, Hettema EH. Pex3-anchored Atg36 tags peroxisomes for degradation in Saccharomyces cerevisiae. EMBO J. 2012 Jun 29;31(13):2852-68. doi: 10.1038/emboj.2012.151. Epub 2012 May, 29. PMID:22643220 doi:http://dx.doi.org/10.1038/emboj.2012.151
- ↑ Kurihara Y, Kanki T, Aoki Y, Hirota Y, Saigusa T, Uchiumi T, Kang D. Mitophagy plays an essential role in reducing mitochondrial production of reactive oxygen species and mutation of mitochondrial DNA by maintaining mitochondrial quantity and quality in yeast. J Biol Chem. 2012 Jan 27;287(5):3265-72. doi: 10.1074/jbc.M111.280156. Epub 2011 , Dec 7. PMID:22157017 doi:http://dx.doi.org/10.1074/jbc.M111.280156
- ↑ Kondo-Okamoto N, Noda NN, Suzuki SW, Nakatogawa H, Takahashi I, Matsunami M, Hashimoto A, Inagaki F, Ohsumi Y, Okamoto K. Autophagy-related protein 32 acts as autophagic degron and directly initiates mitophagy. J Biol Chem. 2012 Mar 23;287(13):10631-8. Epub 2012 Feb 3. PMID:22308029 doi:http://dx.doi.org/10.1074/jbc.M111.299917
- ↑ Kondo-Okamoto N, Noda NN, Suzuki SW, Nakatogawa H, Takahashi I, Matsunami M, Hashimoto A, Inagaki F, Ohsumi Y, Okamoto K. Autophagy-related protein 32 acts as autophagic degron and directly initiates mitophagy. J Biol Chem. 2012 Mar 23;287(13):10631-8. Epub 2012 Feb 3. PMID:22308029 doi:http://dx.doi.org/10.1074/jbc.M111.299917
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