Two distinct mechanisms target the autophagy-related E3 complex to the pre-autophagosomal structure

ELife
Kumi HaradaHitoshi Nakatogawa

Abstract

In autophagy, Atg proteins organize the pre-autophagosomal structure (PAS) to initiate autophagosome formation. Previous studies in yeast revealed that the autophagy-related E3 complex Atg12-Atg5-Atg16 is recruited to the PAS via Atg16 interaction with Atg21, which binds phosphatidylinositol 3-phosphate (PI3P) produced at the PAS, to stimulate conjugation of the ubiquitin-like protein Atg8 to phosphatidylethanolamine. Here, we discover a novel mechanism for the PAS targeting of Atg12-Atg5-Atg16, which is mediated by the interaction of Atg12 with the Atg1 kinase complex that serves as a scaffold for PAS organization. While autophagy is partially defective without one of these mechanisms, cells lacking both completely lose the PAS localization of Atg12-Atg5-Atg16 and show no autophagic activity. As with the PI3P-dependent mechanism, Atg12-Atg5-Atg16 recruited via the Atg12-dependent mechanism stimulates Atg8 lipidation, but also has the specific function of facilitating PAS scaffold assembly. Thus, this study significantly advances our understanding of the nucleation step in autophagosome formation.

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Citations

May 27, 2020·The Journal of Cell Biology·Yui TomiokaHitoshi Nakatogawa
May 27, 2020·Journal of Neural Transmission·Elena PompiliFrancesco Fornai
Jun 9, 2020·Cell Discovery·Taki Nishimura, Sharon A Tooze
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Apr 4, 2021·International Journal of Molecular Sciences·Mehdi EshraghiSaeid Ghavami
Apr 30, 2021·Frontiers in Immunology·LaNisha L PattersonJere W McBride
May 1, 2021·International Journal of Molecular Sciences·Hong ChenTao Wang
May 6, 2021·Cell Discovery·Sascha Martens, Dorotea Fracchiolla
May 11, 2020·Molecular Cell·Debjani Bhattacharya, Christian Behrends
May 27, 2021·Cell Discovery·Taki Nishimura, Sharon A Tooze
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Jan 15, 2022·Journal of Zhejiang University. Science. B·Qianqian ZhengHui Wang

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Methods Mentioned

BETA
fluorescence microscopy
immunoprecipitation
coimmunoprecipitation
two-hybrid
lipidation

Software Mentioned

MetaMorph
Fiji ( ImageJ )
MASCOT

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