A new type of ERGIC–ERES membrane contact mediated by TMED9 and SEC12 is required for autophagosome biogenesis

Abstract

Under stress, the endomembrane system undergoes reorganization to support autophagosome biogenesis, which is a central step in autophagy. How the endomembrane system remodels has been poorly understood. Here we identify a new type of membrane contact formed between the ER-Golgi intermediate compartment (ERGIC) and the ER-exit site (ERES) in the ER-Golgi system, which is essential for promoting autophagosome biogenesis induced by different stress stimuli. The ERGIC-ERES contact is established by the interaction between TMED9 and SEC12 which generates a short distance opposition (as close as 2-5 nm) between the two compartments. The tight membrane contact allows the ERES-located SEC12 to transactivate COPII assembly on the ERGIC. In addition, a portion of SEC12 also relocates to the ERGIC. Through both mechanisms, the ERGIC-ERES contact promotes formation of the ERGIC-derived COPII vesicle, a membrane precursor of the autophagosome. The ERGIC-ERES contact is physically and functionally different from the TFG-mediated ERGIC-ERES adjunction involved in secretory protein transport, and therefore defines a unique endomembrane structure generated upon stress conditions for autophagic membrane formation.

TMED2/9/10 Serve as Biomarkers for Poor Prognosis in Head and Neck Squamous Carcinoma

“…A study found that the cell biological mechanism of misfolded protein cargo entrapment was related to the targeting of TMED9 to the small molecule BRD4780 ( Dvela-Levitt et al, 2019 ). In addition, membrane contact between the ER—Golgi intermediate compartment (ERGIC) and the ER-exit site (ERES) mediated by TMED9 constituted the occurrence of autophagosomes ( Li et al, 2021 ). The transmembrane protein TMED10 was recently identified as a protein channel mediating vesicle translocation and secretion of termed cytosolic leaderless proteins (cytosolic proteins lacking a signal peptide) ( Nguyen and Debnath, 2020 ; Zhang et al, 2020 ).…”

Time-resolved proximity labeling of protein networks associated with ligand-activated EGFR

“…Most recently, a role of TFG in ER-associated autophagy was proposed, further supporting potential involvement of TFG in the crosstalk of the endolysosomal system and ER (Carinci et al, 2021). However, another study suggested that ERES-ER-GIC-associated autophagy does not require TFG (Li et al, 2021). We speculate that the TFG function in the endosomal system, possibly promoting sorting to lysosomal degradation pathway, may be similar to the proposed role of TFG in COPII vesicle uncoating and spatially organizing the ERES-ER-GIC trafficking ''hub.''…”

The many hats of transmembrane emp24 domain protein TMED9 in secretory pathway homeostasis

“…It has long been known that TMED9 participates in ER exit site (ERES) formation for cargo transport to the Golgi (Lavoie et al, 1999;Fujita et al, 2011). However, Li et al (2022) found that ERES-localized Sec12 and ERGIC-localized TMED9 interact directly in trans through their cytoplasmic domains, bringing ERES into close proximity with the ERGIC. ERES-ERGIC association is important for the generation of starvation-induced autophagosomes (Li et al, 2022).…”