Mechanism of autophagy initiation has justbeen revealed11 July 2016

Under nutrient-rich conditions, Atg1, Atg13 and theAtg17-29-31 subcomplex exist without interacting witheach other. Upon autophagy induction, under conditionssuch as starvation, they form a pentameric complex,which further assembles into a giant autophagy initiationmachinery complex. Credit: Developmental Cell

In order to live, it is necessary for creatures notonly to synthesize essential components, but alsodegrade harmful or superfluous components.Autophagy, an intracellular degradation systemconserved among eukaryotes from yeast tohumans, contributes to cell homeostasis viaisolating and degrading various unnecessarycomponents within cells. Since autophagydysfunction is linked to severe diseases such asneurodegeneration and cancer, the artificial controlof autophagy promises to facilitate thedevelopment of therapeutic and preventivetreatment for these and severe diseases.

In budding yeast, the Atg1 complex, comprisingAtg1, Atg13, Atg17, Atg29 and Atg31, mediatesthe initiation of autophagy (Figure 1). Whenautophagy is induced by starvation, these fivecomponents gather to form a dimer of pentamers.However, the formation of the dimer of pentamersalone is not sufficient for autophagy induction: anddozens of the pentameric complexes need toassemble into a supramolecular complex ofautophagy initiation machinery elements. However,the molecular mechanism has been elusive.

This mystery has been addressed by HonoraryProf. Yoshinori Ohsumi and Dr. Hayashi Yamamotoat Tokyo Institute of Technology, and Drs. NobuoN. Noda and Yuko Fujioka at Institute of MicrobialChemistry, in collaboration with other researchers.The researchers focused on Atg13 and analysed itsstructure and function in vitro. The data revealedthat Atg13 has an intrinsically disordered, string-likeconformation in solution and that Atg13 has twodistinct binding regions for Atg17. Detailedanalyses of the interaction between Atg13 andAtg17 by X-ray crystallography uncovered thatAtg13 links two Atg17 molecules to each otherusing two binding regions. Analysis of the size ofthe Atg1 complex revealed that Atg1 complexes arelinked to each other by Atg13, which results in theformation of a huge autophagy initiation complex(Figure 2). When point mutations that impair theformation of this giant complex were introduced toAtg13, association of the autophagy initiationmachinery was completely blocked. These datasuggest that the supramolecular complex resultingfrom the linkage of Atg1 complexes to each otherby Atg13 functions as the autophagy initiationmachinery in vivo.

Atg13 (red) links Atg1 (blue) and two Atg17s (green) toeach other, thereby promoting formation of the giantcomplex. Credit: Developmental Cell

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Next, the function of the autophagy initiationmachinery was studied in budding yeast, revealingthat the phosphorylation activity of Atg1 is markedlyenhanced when it is incorporated into thesupramolecular autophagy initiation complex.Moreover, it was revealed that the autophagyinitiation machinery efficiently recruits Atg9vesicles, which serve as membrane sources forautophagosome formation, and phosphorylatesAtg9. These data collectively suggest that theautophagy initiation machinery not only mediatesformation of initial isolation membrane through therecruitment of Atg9 vesicles, but also promotesautophagosome formation via phosphorylatingautophagy-related factors including Atg9 (Figure 3).

These results are an important step in our quest tofully understand the molecular mechanisms ofautophagy initiation and autophagosome formation.A better understanding of the mechanisms of theinitial steps of autophagy promises to allow thedevelopment of compounds that specificallyregulate autophagy, with exciting clinicalimplications for the treatment of a range of seriousconditions.

The autophagy initiation machinery mediates formation ofthe initial isolation membrane through the recruitment ofAtg9 vesicles. At the same time, the machineryphosphorylates Atg factors including Atg9, therebypromoting autophagosome formation. Credit:Developmental Cell

More information: DOI:10.1016/j.devcel.2016.06.015

Provided by Tokyo Institute of TechnologyAPA citation: Mechanism of autophagy initiation has just been revealed (2016, July 11) retrieved 30 April2022 from https://medicalxpress.com/news/2016-07-mechanism-autophagy-revealed.html

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