# Monitoring and Manipulating the Activity of the Immunoproteasome with Small Molecules

> **NIH NIH R01** · PURDUE UNIVERSITY · 2020 · $373,310

## Abstract

Project Summary
 The proteasome is an essential cellular enzyme complex. Its main function is to degrade proteins that have
been tagged with ubiquitin. When cells receive a signal, typically a cytokine, the expression of a different isoform
of the proteasome, called the immunoproteasome, begins to be produced. The immunoproteasome (iCP)
degrades proteins in a similar fashion as the standard proteasome, but more of its products are compatible to
be loaded into an MHC-I complex. These MHC-I-peptide complexes are used by cells to initiate the adaptive
immune system response by displaying peptides on the cell surface to be recognized by immune cells. The rate
and extent of this type of immune system response is critical. For example, when a virus infects cells, it is
important the immune system responds rapidly to prevent the virus from replicating too quickly. However, if the
immune response is triggered when there is no infection, T-cells can begin to attack and destroy healthy tissue,
leading to autoimmune diseases.
 The inhibition of the immunoproteasome has recently been explored as a potential mechanism to combat
autoimmune diseases. The hypothesis is that if less MHC-I compatible peptides can be produced by the iCP,
the fewer T-cells will be activated/signaled. However, the opposite is true when a viral infection occurs, when an
increase in MHC-I compatible peptides would allow for a rapid immune system response, clearing the virus
before it can infect more cells. In this proposal, we will explore how much iCP activity elicits what level of MHC-
I expression on a cell. To accomplish this, we will utilize our recently developed iCP-activity probe that can be
used in live cells and an antibody to a specific MHC-I-antigen complex using a variety of techniques including
confocal microscopy and a plate reader-based assay. While these studies are ongoing, we will also use our
activity-based iCP probe to screen for molecules that can affect iCP hydrolysis, leading to a decrease or increase
in MHC-I expression.
 Upon completion of the Aims described here, we will for the first time be able to quantify the relationship
between iCP activity and MHC-I expression levels. Additionally, new small molecule inhibitors or stimulators of
the iCP will also be discovered and studied. The long-term goal is to use these newly discovered small molecule
modulators of iCP activity to affect autoimmune diseases and viral infections.

## Key facts

- **NIH application ID:** 10051796
- **Project number:** 1R01AI150847-01A1
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Darci J Trader
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $373,310
- **Award type:** 1
- **Project period:** 2020-07-02 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10051796

## Citation

> US National Institutes of Health, RePORTER application 10051796, Monitoring and Manipulating the Activity of the Immunoproteasome with Small Molecules (1R01AI150847-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10051796. Licensed CC0.

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