A new type of membrane contact in the ER-Golgi system regulates autophagosome biogenesis

Abstract

Formation of the double-membrane autophagosome requires membrane reorganization of the endomembrane system to generate membrane precursors. The ER-Golgi trafficking system has been shown to provide membranes for phagophore growth. Nonetheless, how the components of the ER-Golgi system are redirected toward autophagosome biogenesis remains unclear. Here, we identify a new type of membrane contact formed between the ER-Golgi intermediate compartment (ERGIC) and the ER-exit sites (ERES) under macroautophagy/autophagy-induction conditions. The ERGIC-ERES contact is established by the TMED9-PREB/SEC12 interaction and regulates the biogenesis of the ERGIC-COPII vesicles, which we found previously act as a membrane template for LC3 lipidation and autophagosome formation.

Keywords: Autophagosome; COPII; ERES; ERGIC; SEC12; TMED9; autophagy.

Figure 1.

A model for ERGIC-ERES contact function in autophagosome precursor formation. (A) Under steady-state conditions, the major function of ERGIC and ERES is to support secretory vesicle trafficking. PREB/SEC12 (dark red oval) interacts with MIA2/CTAGE5 (purple oval) to localize to and to maintain concentration in the ERES. TFG (oligomers; orange oval) tethers ERES and COPII vesicles to direct secretory protein cargo transport to the ERGIC. (B-C) Upon starvation, ERGIC and ERES switch their function toward autophagosome biogenesis. (B) First, the ERES is enlarged with the PREB/SEC12-enriched portion surrounding the ERGIC. The process is dependent on RB1CC1 (green oval), which likely tethers ERES compartments via association with PREB/SEC12. MIA2 is also important because it enriches PREB/SEC12 on the ERES. Second, the remodeled ERES forms a contact with the ERGIC via TMED9-PREB/SEC12 interaction. The ERGIC-ERES contact, which is independent of TFG, (I) leads to the relocation of PREB/SEC12 to the ERGIC, and (ii) causes transactivation of COPII vesicle formation on the ERGIC by ERES-localized PREB/SEC12. (C) Third, the ERES-ERGIC contact triggers the assembly of ERGIC-COPII vesicles, which bud from the ERGIC and act as a membrane template for LC3 lipidation. The lipidated vesicles coalesce with other membrane sources, including ATG9-containing vesicles, at the PAS to generate the double membrane autophagosome. As key regulator of the ERGIC-ERES contact, TMED9 localizes on the ERGIC and may transit from the ERGIC-COPII vesicles to the autophagosome. Further effort is needed to test this possibility. COPIv, COPI vesicle; COPIIv, COPII vesicle