# Selenoproteins in the ER-associated protein degradation pathway

> **NIH NIH R01** · UNIVERSITY OF DELAWARE · 2020 · $242,663

## Abstract

PROJECT SUMMARY
The ER is responsible for the folding and posttranslational modification of over a third of all proteins in
eukaryotes. Impaired degradation of proteins is strongly linked to neurodegenerative and protein misfolding
diseases. Here we examine the ER-associated protein degradation (ERAD) pathway, which governs the
extraction of misfolded proteins or misassembled protein complexes from the ER's membrane and lumen and
their transport to the cytoplasm where they are degraded by the proteasome. The ERAD is targeted in cancer
treatments since cancerous cells require an increased capacity for protein folding and degradation.
Two integral membranes proteins that belong to the family of selenoproteins contribute to the ERAD
machinery: selenoprotein S (SelS) and selenoprotein K (SelK). Since all selenoproteins are enzymes SelS and
SelK are most likely catalytically active but their specific contribution to the ERAD pathway is yet unknown. We
recently discovered that SelK is able to cleave its own peptide bond, releasing a selenocysteine–containing
peptide, and thus terminating enzymatic activity. We propose that this autoproteolysis is a regulatory
mechanism responsible for SelK associations with different membrane complexes. We will characterize the
cleavage mechanism, cleavage sites and the unprecedented contribution of selenocysteine to the peptide
bond cleavage. We will then examine whether SelK protein partners affect the cleavage rate or sites and
whether truncated forms of SelK are able to bind selected protein partners.
In a related thrust, we will examine how SelK's protein partner, SelS, coordinates the recruitment of the AAA
ATPase valosin-containing protein (VCP) p97 to the membrane channel that translocates misfolded proteins
(dislocon). The cytoplasmic p97 provides the energy necessary for pulling misfolded protein out of the dislocon
and hence is central to the ERAD process. Because selenoproteins are often found to detoxify or regulate
reactive oxidative species we hypothesize that SelS not only recruits p97 but also regulates its ATPase activity
and sensitivity to oxidative modifications. We will map SelS interactions with p97 and derlin-1, a
transmembrane contributor to the dislocon. Also SelS's ability to interact with additional protein substrates
while bound to p97 or derlin-1 will be assessed.
The proposed experimental work will unveil the molecular interactions between SelS, SelK, derlin-1, and p97,
thus clarifying the steps required for complex assembly of the dislocon and its energy source, p97. In addition,
it will be clarified to what extent SelS acts -in a redox state dependent way- as sensor of oxidants and protects
p97 from damage. Together, our studies will dramatically advance our understanding of SelS's and SelK's
contribution to protein degradation and of the role of their selenocysteine in complex formation and in
enzymatic reactions. Because of the specialized chemistry associated with selenocysteine, SelS...

## Key facts

- **NIH application ID:** 9690137
- **Project number:** 5R01GM121607-03
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Sharon Rozovsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $242,663
- **Award type:** 5
- **Project period:** 2017-07-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9690137

## Citation

> US National Institutes of Health, RePORTER application 9690137, Selenoproteins in the ER-associated protein degradation pathway (5R01GM121607-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9690137. Licensed CC0.

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