# Activation of the NOD1 and NOD2 signaling pathways

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2021 · $226,430

## Abstract

PROJECT SUMMARY
 NOD1 and NOD2 are pattern recognition receptors that sense fragments of bacterial peptidoglycans,
and are able to detect perturbations in cellular processes such as the modulation of the actin cytoskeleton and
disturbance in endoplasmic reticulum (ER) homeostasis. Under different stressful conditions, such as bacterial
and viral infections, protein misfolding and perturbations in calcium homeostasis, the ER is unable to maintain
homeostasis and activates the unfolded protein response (UPR). Upon ER stress three transmembrane
receptors, IRE1, PERK and ATF6 are activated and regulate biological processes such as inhibition of protein
translation, autophagy, and inflammation to reestablish cellular homeostasis. NOD1 and NOD2 have been
implicated in ER stress-induced inflammation, by acting downstream in the UPR to induce NF-B activation
and IL-6 production. The exact mechanism how NOD1 and NOD2 can sense ER stress is currently unknown.
NOD1 and NOD2 can also sense the activation of small Rho GTPases such as Rac1. Rac1 activation leads to
membrane ruffling as well as activation of the transcription factor NF-B. We and others have shown that
NOD1 and NOD2 interact with Rac1 at the cell membrane. The underlying mechanism of Rac1-mediated
NOD1 and NOD2 activation is currently unknown. In the application we propose to study the mechanisms of
peptidoglycan-independent activation of NOD1 and NOD2 by modulation of the actin cytoskeleton and
thapsigargin-induced ER stress. Our central hypothesis is that NOD1 and NOD2 can detect cellular
perturbations independent of peptidoglycan recognition. We will test key aspects of our hypothesis using the
logical and innovative approach outlined in the following specific aims.
 Specific Aim 1. Determine the role of NOD1 and NOD2 in sensing ER stress. We will determine the
contribution of calcium flux from the ER to the mitochondria in ER stress induced NOD1 and NOD2 activation.
We will test our hypothesis that mitochondria damaged by ER stress release damage-associated molecular
patterns (DAMPs) that activate NOD1 and NOD2.
 Specific Aim 2. Perturbations in cellular processes determines NOD1 and NOD2 localization. We
will investigate the cellular localization of NOD1 and NOD2 in cells treated with thapsigargin to induce ER
stress and in cells that express active Rac1 or Rac1 mutant forms that either induce cytoskeletal remodeling or
NF-B activation. Characterizing and understanding the mechanisms of peptidoglycan-independent NOD1 and
NOD2 activation provides a plausible explanation for the observation that viruses and parasites trigger NOD1
and NOD2 signaling. These findings are innovative new concepts and would markedly influence the current
concepts of NOD1 and NOD2 biology.

## Key facts

- **NIH application ID:** 10172844
- **Project number:** 5R21AI154043-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Arina Marijke Keestra-Gounder
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $226,430
- **Award type:** 5
- **Project period:** 2020-06-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172844

## Citation

> US National Institutes of Health, RePORTER application 10172844, Activation of the NOD1 and NOD2 signaling pathways (5R21AI154043-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10172844. Licensed CC0.

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