# Regulation of innate immunity by a novel protein interaction network

> **NIH NIH R21** · NATIONAL JEWISH HEALTH · 2020 · $205,000

## Abstract

ABSTRACT
 The goal of this proposal is to elucidate the mechanisms by which the novel innate immune regulator,
Siah1, enhances Toll-like receptor (TLR) signaling and host defense. Siah1 is the central hub in a novel innate
immunity protein interaction network that we identified using comparative genomics RNAi screens in C.
elegans and mouse macrophages. This protein interaction network contains several proteins in the canonical
TLR signaling pathway as well as many novel interacting proteins including Siah1. Siah1 is an E3 ubiquitin
ligase that binds to the TLR signaling adaptor MyD88; we have shown that Siah1 enhances innate immunity
and host defense in C. elegans and mouse macrophages. In particular, we have found that mutation of Siah1
renders C. elegans more susceptible to several bacterial pathogens. We hypothesize that Siah1 enhances
the ubiquitination and subsequent proteolysis of an inhibitor of TLR signaling. We propose to determine
how Siah1 regulates TLR4 signaling by (1) identifying the TLR4 signaling protein(s) whose ubiquitination and
stability is regulated by Siah1, and (2) determine the mechanism used by Siah1 and its target(s) to regulate
innate immunity. These studies represent a critical step towards our goal of establishing the genes in the Siah1
innate immunity protein interaction network as new therapeutic or diagnostic targets for a variety of infectious
and inflammatory diseases.

## Key facts

- **NIH application ID:** 9873916
- **Project number:** 5R21AI132827-02
- **Recipient organization:** NATIONAL JEWISH HEALTH
- **Principal Investigator:** Scott Alper
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $205,000
- **Award type:** 5
- **Project period:** 2019-02-18 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9873916

## Citation

> US National Institutes of Health, RePORTER application 9873916, Regulation of innate immunity by a novel protein interaction network (5R21AI132827-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9873916. Licensed CC0.

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