# Discovery of Novel Mechanisms of Action of Ubiquitin-Like Proteins in Cellular Stress Pathways

> **NIH NIH R35** · UNIVERSITY OF IOWA · 2020 · $385,828

## Abstract

PROJECT SUMMARY
Eukaryotic cellular stress responses are highly conserved and precisely regulated. When these pathways
malfunction there are often grave physiological consequences in the form of diseases such as cancer,
neurodegenerative disease and autoimmune disorders. Ubiquitin-like modifications (UBLs) are rapid, reversible
and can profoundly alter cell fate and function. Intriguingly, the majority of UBLs are involved in the cellular
response to stress, in particular the response to infection, ER-stress and autophagy. Ubiquitin-like proteins share
structural conservation with ubiquitin and also covalently modify target proteins, however UBLs have extremely
divergent functions, which range from transcriptional repression to autophagy initiation. Unlike ubiquitin, the
consequences of ISGylation or ATG12ylation on target protein fate and function are largely unknown. In this
proposal, we aim to decode the post-translational landscape of the cell following eukaryotic stress responses
using sophisticated proteomics strategies to address the fundamental question of how ISG15 and ATG12 alter
the function of their covalent cellular targets.
For ISG15, my laboratory’s recent work identified a novel role in the control of host metabolic processes and this
proposal addresses how ISGylation of mTOR and other key upstream regulators of the catabolic process of
autophagy tunes the metabolic and catabolic capacity of cells and animals.
For ATG12, we have pioneered an in vivo genetic method coupled with cutting-edge proteomics to identify
endogenous substrates of the autophagy-related ubiquitin-like protein ATG12 following induction of cellular
stress pathways such as mitochondrial outer membrane permeabilization or endoplasmic reticulum stress.

## Key facts

- **NIH application ID:** 10027440
- **Project number:** 1R35GM137961-01
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Lilliana RADOSHEVICH
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,828
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10027440

## Citation

> US National Institutes of Health, RePORTER application 10027440, Discovery of Novel Mechanisms of Action of Ubiquitin-Like Proteins in Cellular Stress Pathways (1R35GM137961-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10027440. Licensed CC0.

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