# Probing organismal proteostasis through the response to intracellular infection

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2023 · $328,615

## Abstract

Project Summary/Abstract
 Aging-related diseases are associated with disruptions in protein homeostasis, or proteostasis. A major
disruptor of proteostasis is infection with intracellular pathogens, but it is poorly understood how responses to
these infections may promote proteostasis. Our long-term goal is to dissect how responses to infection and
other proteotoxic stressors can protect overall organismal health and lifespan through characterizing a novel
proteostasis response we discovered in the nematode C. elegans called the Intracellular Pathogen Response
or IPR. Our previous work demonstrated how upregulation of IPR genes that encode components of a cullin
ring ubiquitin ligase promote improved proteostasis, including increased thermotolerance. The objective of this
proposal is to determine how this multi-subunit ubiquitin ligase is assembled, to identify its target(s), and to
elucidate the fate of those targets and how they impact thermotolerance. The central hypothesis is that
intracellular infection and other specific proteotoxic stressors induce mRNA expression of ubiquitin ligase
subunits including: 1) the Cullin CUL-6, 2) the RING domain protein RCS-1, 3) a Skp-Related Protein SKR-3, 4
or 5, and 4) F-Box Proteins FBXA-75 or FBXA-158; and that redox-dependent dimerization of this CUL-6-
containing ubiquitin ligase tetramer (to create an enzyme complex of eight subunits total) leads to its activation,
and that this enzyme complex ubiquitylates a yet-to-be identified target that is then degraded by the lysosome
to regulate proteostasis. The rationale is based on our published genetic and biochemical data about the
assembly and function of RCS-1/CUL-6/SKR-3,4,5/FBXA-75/158, and our unpublished in vitro and in vivo data
about redox-dependent dimerization of SKR-3, together with our unpublished genetic and pharmacological
data indicating that the increased thermotolerance mediated by the CUL-6 ubiquitin ligase is dependent on the
lysosome. Our work is innovative because we are pursuing the IPR, which is a recently described proteostasis
response acting independently of canonical proteostasis pathways like the heat shock response and unfolded
protein responses.
 We will test our hypothesis with three specific aims including Aim 1) Determine the dimerization,
interactions and function of SKR-3, SKR-4, SKR-5, FBXA-75 and FBXA-158, both in vitro and in vivo; Aim 2)
Identify the target(s) of the CUL-6 ubiquitin ligase; and Aim 3) Characterize the downstream fate of these
targets, including possible degradation by the lysosome. The expected outcome is to determine which SKR
proteins heterodimerize, which SKR protein interacts with which F-box protein, which proteins are targeted by
this ubiquitin ligase complex, and which autophagy factors and other cellular components are involved in
directing targets to the lysosome. The proposed research is significant, because it could lead to new
treatments for aging-related diseases associated with disrupti...

## Key facts

- **NIH application ID:** 10665771
- **Project number:** 5R01AG052622-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Emily R Troemel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $328,615
- **Award type:** 5
- **Project period:** 2016-09-30 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10665771

## Citation

> US National Institutes of Health, RePORTER application 10665771, Probing organismal proteostasis through the response to intracellular infection (5R01AG052622-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10665771. Licensed CC0.

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