Emerging mechanisms of COPII adaptation for large cargo ER export

Export of secretory proteins from the endoplasmic reticulum is mediated by the COPII coat which must accommodate diverse cargoes. While small COPII vesicles are well characterised, they do not explain ER exit of exceptionally large and abundant cargoes such as procollagens. Recent work has expanded the classic vesicular model of COPII-mediated secretion toward a more flexible view of the COPII coat architecture, in which cell- and cargo-specific regulators of coat turnover and membrane tethers can remodel ER exit sites (ERES) to meet cargo-specific demands. Multicellular organisms have evolved an expanded network of COPII paralogues and interacting proteins such as SURF4, TMEM proteins, and TANGO1 that may generate enlarged carriers, membrane tubules, or transient intercompartmental continuities for large cargo exit from the ER. This review highlights recent progress and remaining gaps in understanding how COPII is regulated to mediate ER export of large cargo and identifies priorities for future investigation.