Related Experiment Video

Updated: May 17, 2026

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
11:36

In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones

Published on: July 25, 2019

A discrete ubiquitin-mediated network regulates the strength of NOD2 signaling

Justine T Tigno-Aranjuez1, Xiaodong Bai, Derek W Abbott

  • 1Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.

Molecular and Cellular Biology
|October 31, 2012
PubMed

Insights

NOD2 signaling dysregulation drives inflammatory diseases. This study reveals ITCH E3 ligase targets cIAP1 for degradation, controlling NOD2 pathway strength and offering therapeutic insights.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cellular Signaling

Background:

  • NOD2 signaling pathway is crucial in inflammatory diseases like Crohn's disease.
  • Inhibitor-of-apoptosis (IAP) proteins, especially cIAP1, are key mediators in NOD2 signaling.
  • Dysregulated NOD2 signaling presents therapeutic opportunities targeting downstream proteins.

Purpose of the Study:

  • To elucidate the molecular mechanism regulating cIAP1 within the NOD2 signaling pathway.
  • To investigate the role of the E3 ubiquitin ligase ITCH in controlling cIAP1 stability.
  • To identify therapeutic strategies for hyperactive NOD2 signaling states.

Main Methods:

  • Investigated cIAP1 regulation by ITCH in NOD2 signaling.
  • Utilized pharmacologic inhibition of cIAP1 in ITCH-deficient macrophages.
  • Performed transcriptome analysis to identify targeted pathways.

Main Results:

  • cIAP1 promotes RIP2 phosphorylation and NOD2 signaling.
  • ITCH ubiquitinates cIAP1, leading to its lysosomal degradation, thus attenuating NOD2 signaling.
  • Pharmacologic cIAP1 inhibition reduced inflammatory responses in ITCH-deficient macrophages.
  • Transcriptome analysis defined cIAP1-targeted pathways within NOD2 signaling.

Conclusions:

  • A ubiquitin-regulated network involving ITCH and cIAP1 controls NOD2 signaling strength.
  • cIAP1 is a critical regulator of NOD2-mediated inflammatory responses.
  • Findings suggest repurposing cIAP1-targeted therapies for inflammatory diseases with hyperactive NOD2 signaling.

More Related Videos

Comparative Strategies for Ubiquitination Detection in Mammalian Cell Lysates Using SMAD2/SMURF2 as a Model09:00

Comparative Strategies for Ubiquitination Detection in Mammalian Cell Lysates Using SMAD2/SMURF2 as a Model

Published on: April 17, 2026

Detection of Protein Ubiquitination09:00

Detection of Protein Ubiquitination

Published on: August 19, 2009

Related Concept Videos

NF-κB-dependent Signaling Pathway02:26

NF-κB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
NF-kB-dependent Signaling Pathway02:26

NF-kB-dependent Signaling Pathway

The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...