# Exploiting bacterial effector proteins to study human ubiquitin signaling

> **NIH NIH R35** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $49,811

## Abstract

Project Summary
 Post-translational signaling through ubiquitination is essential to all eukaryotic life, and dysregulation of this
process can lead to severe forms of disease. The far-reaching importance of ubiquitin signaling across many
cellular processes stems from its ability to form a diverse set of polymeric chains that signal for distinct outcomes.
The complexity of ubiquitin signaling vastly outweighs our understanding of its regulation and cellular outcomes.
While the signaling roles for some ubiquitin chain types are known (e.g. protein degradation or cell cycle
regulation), the functions of many so-called `atypical' chains have remained a mystery despite decades of
research. As an alternative approach to studying fundamental human biology, we study the interactions between
invading pathogenic bacteria and the host ubiquitin signaling network. In addition to a range of other ubiquitin-
targeted activities, to support infection bacteria have evolved secreted effector proteins to assemble and remove
host ubiquitin signals, in some cases with exquisite specificity toward discrete ubiquitin chain types. We propose
that ubiquitin-targeted bacterial effectors represent a rich opportunity to study human ubiquitin signaling from an
`outside-in' perspective. To explore this opportunity, we have developed a multipronged approach that has
identified novel ubiquitin-targeted activities among important bacterial pathogens. Using structural and
biochemical approaches we will explain the mechanisms and specificities of these bacterial enzymes, at which
point they will be used as case studies and tools to extend our work toward deciphering the regulatory and
signaling complexities of the human ubiquitin system. Our innovative approach to studying ubiquitin biology plays
to our strengths in the biochemical mechanisms of its regulation, and leverages the strong evolutionary pressure
placed on bacteria to usurp specific aspects of host ubiquitin signaling. Over the next five years we will
demonstrate the breadth of bacterial ubiquitin-targeted activities and their utility for dissecting the intricacies of
ubiquitin signaling, which feeds into our larger vision of understanding the motivations and ramifications of
bacterial interference in host signaling processes.

## Key facts

- **NIH application ID:** 11034898
- **Project number:** 3R35GM142486-04S1
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Jonathan N Pruneda
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $49,811
- **Award type:** 3
- **Project period:** 2021-07-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11034898

## Citation

> US National Institutes of Health, RePORTER application 11034898, Exploiting bacterial effector proteins to study human ubiquitin signaling (3R35GM142486-04S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11034898. Licensed CC0.

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