# CNX:FAM134B-driven ERLAD of ATZ polymers proceeds via enhanced formation of VAPA:ORP1L:RAB7 contact sites between ER and endolysosomes

## TL;DR

The paper reveals a new mechanism by which misfolded proteins are transported from the endoplasmic reticulum to lysosomes for degradation.

## Contribution

A novel function of ER-endolysosome membrane contact sites in ER-to-lysosome-associated degradation is identified.

## Key findings

- The VAPA:ORP1L:RAB7 complex forms contact sites between ER and endolysosomes.
- The CNX-FAM134B-LC3 complex facilitates ER-to-lysosome transfer of misfolded ATZ polymers.
- Membrane fusion via SNARE proteins STX17 and VAMP8 is required for efficient degradation.

## Abstract

Membrane contact sites (MCS) between organelles maintain the proximity required for controlled exchange of small molecules and ions yet preventing fusion events that would compromise organelles’ identity and integrity. Here, by investigating the intracellular fate of the disease-causing Z-variant of alpha1 antitrypsin (ATZ), we report on a novel function of MCS between the endoplasmic reticulum (ER) and RAB7/LAMP1-positive endolysosomes in ER-to-lysosome-associated degradation (ERLAD). For this function, the VAPA:ORP1L:RAB7 multi-protein complex forming MCS between the ER and endolysosomes engages, in an ERLAD client-driven manner, the misfolded protein segregation complex formed by the lectin chaperone calnexin (CNX), the ER-phagy receptor FAM134B, and the ubiquitin-like protein LC3. Generation of this supramolecular complex facilitates the membrane fusion events regulated by the SNARE proteins STX17 and VAMP8 that ensure efficient delivery of ATZ polymers from their site of generation, the ER, to the site of their intracellular clearance, the degradative RAB7/LAMP1-positive endolysosomes.