# ER and post-ER quality control of integral membrane proteins

> **NIH NIH R35** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $368,432

## Abstract

Approximately one-third of all newly synthesized proteins in eukaryotes enter the endoplasmic
reticulum (ER). Once associated with this compartment, these nascent polypeptides are post-
translationally processed, acquire their native confirmations, oligomerize, and are sorted for
extracellular secretion or delivery to other organelles. However, many disease-causing
mutations compromise protein folding and maturation, which in turn can generate aggregation-
prone species. To off-set the catastrophic effects that accompany the accumulation of protein
aggregates, misfolded protein substrates are: (i) selected by molecular chaperones associated
with the ER, (ii) modified with ubiquitin, (iii) delivered to the cytoplasm via a process known as
retrotranslocation, and (iv) degraded by the 26S proteasome. Brodsky and colleagues named
this pathway ER associated degradation (ERAD), and over the past 21 years many of the
molecular mechanisms underlying this sequence of events were defined in the Brodsky lab. To
date, ~80 human diseases are linked to the ERAD pathway and >1,200 publications have been
authored on various aspects of this pathway. Ongoing efforts are defining the
pathophysiological foundation of several ERAD-related disorders. In parallel, members of the
Brodsky lab have revealed how key components orchestrate each step during ERAD. In the
past 5 years, the lab has published 64 papers, and tools and technologies were developed that
provide an unprecedented view of the mechanisms that lead to the selection, ubiquitination,
retrotranslocation, and degradation of diverse substrates. Nevertheless, recent discoveries
dictate that more challenging research directions are pursued: By necessity, these next efforts
will require additional method development and a pursuit of longer-term goals. Specific
questions that the research program will address include: What biochemical features define an
ERAD substrate? Which factors are sufficient to drive the retrotranslocation of ERAD substrates,
some of which are aggregation-prone? Do ER-associated proteases function in tandem with the
26S proteasome to destroy substrates that are stably integrated into the ER membrane, and
thus might be retrotranslocation resistant? And, how are retrotranslocated membrane proteins—
which can reside in the cytosol after being liberated from the ER—retained in a soluble state?
Answers to these questions, which lie at the core of research in the field, will significantly
advance an understanding of how cellular health is maintained in the face of proteotoxic stress
as well as how ERAD-associated diseases arise and might be rectified.

## Key facts

- **NIH application ID:** 10428489
- **Project number:** 5R35GM131732-04
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** JEFFREY L. BRODSKY
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $368,432
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10428489

## Citation

> US National Institutes of Health, RePORTER application 10428489, ER and post-ER quality control of integral membrane proteins (5R35GM131732-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10428489. Licensed CC0.

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