Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex

Yun Zhong, Qing Jun Wang, Xianting Li, Ying Yan, Jonathan M. Backer, Brian T. Chait, Nathaniel Heintz, Zhenyu Yue

Research output: Contribution to journalArticle

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Abstract

Beclin 1, a mammalian autophagy protein that has been implicated in development, tumour suppression, neurodegeneration and cell death, exists in a complex with Vps34, the class III phosphatidylinositol-3-kinase (PI(3)K) that mediates multiple vesicle-trafficking processes including endocytosis and autophagy. However, the precise role of the Beclin 1-Vps34 complex in autophagy regulation remains to be elucidated. Combining mouse genetics and biochemistry, we have identified a large in vivo Beclin 1 complex containing the known proteins Vps34, p150/Vps15 and UVRAG, as well as two newly identified proteins, Atg14L (yeast Atg14-like) and Rubicon (RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein). Characterization of the new proteins revealed that Atg14L enhances Vps34 lipid kinase activity and upregulates autophagy, whereas Rubicon reduces Vps34 activity and downregulates autophagy. We show that Beclin 1 and Atg14L synergistically promote the formation of double-membraned organelles that are associated with Atg5 and Atg12, whereas forced expression of Rubicon results in aberrant late endosomal/lysosomal structures and impaired autophagosome maturation. We hypothesize that by forming distinct protein complexes, Beclin 1 and its binding proteins orchestrate the precise function of the class III PI(3)K in regulating autophagy at multiple steps.

Original languageEnglish (US)
Pages (from-to)468-476
Number of pages9
JournalNature Cell Biology
Volume11
Issue number4
DOIs
StatePublished - 2009

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Phosphatidylinositol 3-Kinase
Autophagy
Yeasts
Class III Phosphatidylinositol 3-Kinases
Fungal Proteins
Endocytosis
Organelles
Biochemistry
Cysteine
Beclin-1
Carrier Proteins
Proteins
Cell Death
Phosphotransferases
Up-Regulation
Down-Regulation
Lipids

ASJC Scopus subject areas

  • Cell Biology

Cite this

Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. / Zhong, Yun; Wang, Qing Jun; Li, Xianting; Yan, Ying; Backer, Jonathan M.; Chait, Brian T.; Heintz, Nathaniel; Yue, Zhenyu.

In: Nature Cell Biology, Vol. 11, No. 4, 2009, p. 468-476.

Research output: Contribution to journalArticle

Zhong, Yun ; Wang, Qing Jun ; Li, Xianting ; Yan, Ying ; Backer, Jonathan M. ; Chait, Brian T. ; Heintz, Nathaniel ; Yue, Zhenyu. / Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. In: Nature Cell Biology. 2009 ; Vol. 11, No. 4. pp. 468-476.
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