Remodeling of ER ‐exit sites initiates a membrane supply pathway for autophagosome biogenesis

• DOI: 10.15252/embr.201744559
• Publication Date: 2017-07-29T00:10:26Z
• Authors: Liang Ge; Min Zhang; Samuel J Kenny; Dawei Liu; Miharu Maeda; Kota Saito; Anandita Mathur; Ke Xu; Randy Schekman
• Keywords: autophagy; autophagosome; ER-exit sites; Vesicular Transport Proteins; Autophagy-Related Proteins; Golgi Apparatus; Endoplasmic Reticulum; 03 medical and health sciences; ER‐exit sites; Antigens, Neoplasm; Autophagy; COPII; Humans; FIP200; Antigens; 2. Zero hunger; Microscopy; 0303 health sciences; Membranes; Organelle Biogenesis; Autophagosomes; Membrane Proteins; Protein-Tyrosine Kinases; Neoplasm Proteins; Protein Transport; Hela Cells; Neoplasm; Generic health relevance; Biochemistry and Cell Biology; COP-Coated Vesicles; Microtubule-Associated Proteins; Developmental Biology; HeLa Cells

AbstractAutophagosomes are double-membrane vesicles generated during autophagy. Biogenesis of the autophagosome requires membrane acquisition from intracellular compartments, the mechanisms of which are unclear. We previously found that a relocation of COPII machinery to the ER-Golgi intermediate compartment (ERGIC) generates ERGIC-derived COPII vesicles which serve as a membrane precursor for the lipidation of LC3, a key membrane component of the autophagosome. Here we employed super-resolution microscopy to show that starvation induces the enlargement of ER-exit sites (ERES) positive for the COPII activator, SEC12, and the remodeled ERES patches along the ERGIC. A SEC12 binding protein, CTAGE5, is required for the enlargement of ERES, SEC12 relocation to the ERGIC, and modulates autophagosome biogenesis. Moreover, FIP200, a subunit of the ULK protein kinase complex, facilitates the starvation-induced enlargement of ERES independent of the other subunits of this complex and associates via its C-terminal domain with SEC12. Our data indicate a pathway wherein FIP200 and CTAGE5 facilitate starvation-induced remodeling of the ERES, a prerequisite for the production of COPII vesicles budded from the ERGIC that contribute to autophagosome formation.