# Quality control in the secretory pathway

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $65,310

## Abstract

Abstract
 The endoplasmic reticulum (ER) is a major site for protein folding and maturation within the cell, and a
wide array of human diseases, including neurodegenerative diseases, familial protein folding disorders, and
diabetes, are associated with disruptions to ER protein folding homeostasis. Endoplasmic reticulum associated
degradation (ERAD) is a highly conserved pathway that functions to promote protein homeostasis by
preventing misfolded protein accumulation. It is an integral part of the ER unfolded protein stress response. In
addition to degradation of misfolded proteins, ERAD regulates the protein levels of ER-resident enzymes, such
as the HMG-CoA reductase, the rate-limiting enzyme in sterol synthesis. Interestingly, the ERAD machinery is
hijacked by viral pathogens during infection, meaning it is a potential therapeutic target.
 The process of ERAD involves transferring target protein substrates from the ER lumen or membrane
to the cytosol for degradation. It can be divided into five distinct steps: substrate recognition, retro-translocation
across the ER membrane, polyubiquitination, extraction from the membrane, and proteasomal degradation.
While the molecular details of the later steps have become increasingly clear, how ERAD machinery
recognizes misfolded or other substrate targets remains ambiguous. Previous work identified substrate
glycosylation state as an important influencer of interactions with ERAD machinery. Nevertheless,
glycosylation is dispensable for degradation, while substrate misfolding is not. The aims of this proposal seek
to identify principles of substrate recognition by ERAD and other protein quality control machinery in the
secretory pathway. Combining DNA sequencing technology and cell sorting techniques, we will generate and
screen libraries of mutated or degron-fused non-ERAD substrates in S. cerevisiae to identify features that are
recognized by ERAD machinery. We will then validate features through cell biology and in vitro reconstitution
assays. Understanding the principles of substrate recognition by ERAD will illuminate the physiological ERAD
targets, should allow us to predict additional targets in higher organisms, and understand exploitation of the
system by certain pathogens.

## Key facts

- **NIH application ID:** 9908930
- **Project number:** 1F32GM136020-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Rachel Starr Plumb
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 1
- **Project period:** 2019-12-11 → 2022-12-10

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9908930

## Citation

> US National Institutes of Health, RePORTER application 9908930, Quality control in the secretory pathway (1F32GM136020-01). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9908930. Licensed CC0.

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