# Mechanisms of immunoproteasome-mediated metabolic disorders

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2021 · $385,694

## Abstract

ABSTRACT
The immunoproteasome is an inducible type of proteasome whose expression is enhanced by inflammation
and oxidative stress. Although the immunoproteasome was found about 30 years ago, the function of the
immunoproteasome is poorly understood except its role in producing antigenic peptides. Recent studies
have shown that the immunoproteasome regulates cell signaling, differentiation and cytokine secretion in
non-immune cells. We found that 95% of proteasome is the immunoproteasome in the mouse liver when
mTORC1 is constitutively active. Numerous mutations and polymorphisms have been identified in
immunoproteasome-specific genes among human populations of metabolic, autoimmune, and rare
diseases. The immunoproteasome level is highly increased in proportion to the degree of inflammation in
liver biopsies from patients who have chronic active hepatitis or cirrhosis. Despite the relevance of the
immunoproteasome in many human diseases, its functions remain poorly understood mainly due to the lack
of knowledge on its target substrates. The objective of this proposed study is to determine the mechanism
by which the immunoproteasome digests its preferential target proteins and determine how the selective
digestion impairs hepatic and global energy metabolism. We developed mice where the immunoproteasome
is depleted specifically in the liver. Interestingly, the depletion of hepatic immunoproteasome led to
beneficial metabolic outcomes protecting the mice against obesity, insulin resistance and steatosis. As a
possible mechanism, we hypothesize that the immunoproteasome induces metabolic reprogramming by
selective digestion of proteins involved in metabolic homeostasis and anti-inflammation. We have three
specific aims to address the hypothesis. First, we will define the immunoproteasome as a crucial mediator
that impairs hepatic lipid metabolism using a genetic mouse model, primary hepatocytes, and
immunoproteasome inhibitors. Second, we will determine the role of the immunoproteasome in oxidative
stress-induced insulin resistance. Based on our preliminary study, we hypothesize that the
immunoproteasome suppresses Akt-dependent metabolism in chronic oxidative stress or inflammation.
Using genetic and chemical approaches, we will demonstrate that the immunoproteasome negatively
regulates Akt signaling under oxidative stress and define the immunoproteasome as a promising therapeutic
target for insulin resistance. Third, we will use quantitative proteomics and proximity-based labeling
methods to comprehensively identify target proteins of the immunoproteasome. We will choose a handful
identified proteins and validate them as targets of the immunoproteasome. The identified proteins will allow
us to define novel metabolic pathways regulated by the immunoproteasome. The outcomes will innovate
our understanding of the immunoproteasome by defining the immunoproteasome as a key mediator and as
a promising therapeutic target for inflammatory metabolic disea...

## Key facts

- **NIH application ID:** 10139030
- **Project number:** 5R01DK125039-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Do-Hyung Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,694
- **Award type:** 5
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10139030

## Citation

> US National Institutes of Health, RePORTER application 10139030, Mechanisms of immunoproteasome-mediated metabolic disorders (5R01DK125039-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10139030. Licensed CC0.

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