# Mechanisms of COPII-Dependent Quality Control and ER Export

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2022 · $495,960

## Abstract

Mechanisms of COPII-Dependent Quality Control and ER Export
The sorting and transport of biosynthetic cargo from the endoplasmic reticulum (ER) is central to eukaryotic
cell physiology. This proposal is focused on the conserved mechanisms and machinery molecules, in particular
the COPII vesicular coat proteins, responsible for the controlled export of thousands of distinct cargo proteins
from the ER. Newly synthesized proteins are subject to quality control (QC) interrogations that may involve
repeated attempts at chaperone-mediated folding, or that target aberrantly folded forms for destruction by ER-
associated degradation (ERAD) (1). It is also the case that QC decisions are made at ER exit sites, as the
COPII coat and associated machinery proteins actively exclude misfolded cargo from vesicles (2, 3). The
mechanisms that control segregation of folded cargo from ER chaperones and misfolded proteins, and their
contribution to ER quality control, are not well understood. This research will address central questions of
COPII trafficking relevant to cell physiology and pathophysiology. The specific aims of the proposal are to: (Aim
1) carry out a structure-function mapping of COPII·machinery interactions, with which to construct a pseudo-
atomic model of the COPII vesicle interior. Building on prior work we will complete the mapping for all 12 major
transmembrane protein constituents of COPII vesicles (22). We will identify ER export motifs on the circulating
ER-Golgi receptor proteins Erv41/Erv46, Rer1 and Erv29, and determine their crystal structures in complex
with COPII protein. Functional relevance will be tested definitively in COPII budding reconstitutions and whole
cell experiments; (Aim 2) investigate the mechanism of COPII protein sorting that imposes ER retention, and
explore its contribution to QC. We will test the complex interplay of cargo, chaperones and COPII-associated
machinery that underlies ER retention (2), exploiting a set of tools developed in the initial phase of research—
in particular, a novel series of small molecules that bind COPII protein to reduce the stringency of ER retention.
We will investigate the capacity of the retention and retrieval systems, the breakdown of retention in UPR-
activated cells, and we will test our working model that chaperone complexes are excluded from vesicles
because they are too large to partition into the interstices of a COPII-associated luminal array; and (Aim 3)
develop the new idea of COPII cargo uptake by enhanced partitioning as an alternative to the bulk flow model
for ER exit. The ER-to-Golgi transport step is essential for eukaryotic cell growth and function, thus the
proposed studies have considerable relevance to human cell physiology and to understanding diseases of
protein mistrafficking and proteotoxicity.

## Key facts

- **NIH application ID:** 10318982
- **Project number:** 5R01GM130905-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** JONATHAN D GOLDBERG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $495,960
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318982

## Citation

> US National Institutes of Health, RePORTER application 10318982, Mechanisms of COPII-Dependent Quality Control and ER Export (5R01GM130905-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10318982. Licensed CC0.

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