Mechanisms of Autophagy

Youle, Richard James

Abstract

Belcin1 is essential for autophagosome membrane expansion. Beclin1 is known to form a complex with VPS34 and ATG14 and its recruitment to membranes is dependent on ATG14. We have found that a novel domain of Beclin1 is required for membrane binding and for autophagy induction. We have confirmed that the autophagy activity and membrane targeting function of this domain is conserved in the yeast orthologue of Beclin1, ATG6. Fusion of this domain to the apoptosis inducing protein Bax spontaneously activated Bax indicating that this domain can target mitochondrial membranes. We have also collaborated in the identification of a role of HSP90 in mitophagy. We are also exploring how mitochondrial fission is coupled to selective autophagy of mitochondria.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Neurological Disorders and Stroke (NINDS)
• Type: Investigator-Initiated Intramural Research Projects (ZIA)
• Project #: 1ZIANS003127-01
• Application #: 8342296
• Support Year: 1
• Fiscal Year: 2011
• Total Cost: $714,426

Institution

• Name: National Institute of Neurological Disorders and Stroke

Publications

Sekine, Shiori; Youle, Richard J (2018) PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol. BMC Biol 16:2

Sarraf, Shireen A; Youle, Richard J (2018) Parkin mediates mitophagy during beige-to-white fat conversion. Sci Signal 11:

Yamano, Koji; Wang, Chunxin; Sarraf, Shireen A et al. (2018) Endosomal Rab cycles regulate Parkin-mediated mitophagy. Elife 7:

Stolz, Alexandra; Putyrski, Mateusz; Kutle, Ivana et al. (2017) Fluorescence-based ATG8 sensors monitor localization and function of LC3/GABARAP proteins. EMBO J 36:549-564

Yao, Yong; Nisan, Danielle; Fujimoto, Lynn M et al. (2016) Characterization of the membrane-inserted C-terminus of cytoprotective BCL-XL. Protein Expr Purif 122:56-63

Murphy, Elizabeth; Ardehali, Hossein; Balaban, Robert S et al. (2016) Mitochondrial Function, Biology, and Role in Disease: A Scientific Statement From the American Heart Association. Circ Res 118:1960-91

Lazarou, Michael; Sliter, Danielle A; Kane, Lesley A et al. (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309-314

Nezich, Catherine L; Wang, Chunxin; Fogel, Adam I et al. (2015) MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5. J Cell Biol 210:435-50

Yamano, Koji; Fogel, Adam I; Wang, Chunxin et al. (2014) Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. Elife 3:e01612

Shen, Qinfang; Yamano, Koji; Head, Brian P et al. (2014) Mutations in Fis1 disrupt orderly disposal of defective mitochondria. Mol Biol Cell 25:145-59