Heat shock protein 90 associates with monarch-1 and regulates its ability to promote degradation of NF-kappaB-inducing kinase.

Abstract

Monarch-1/NLRP12 is expressed in myeloid cells and functions as a negative regulator of inflammation by inducing proteasome-mediated degradation of NF-kappaB-inducing kinase. Monarch-1 is a member of the CATERPILLER gene family, also known as the nucleotide-binding domain leucine-rich repeat gene family. This family shares strong structural homology to major immune regulators expressed in lower organisms, including plants. In plants, these disease-resistance proteins (R proteins) sense pathogenic insult and initiate a protective response to limit pathogen growth. To perform this role, many R proteins require the highly conserved chaperone molecule, heat shock protein (Hsp) 90. Using a two-dimensional gel/mass spectrometry system, we detected the association of the nucleotide-binding domain leucine-rich repeat protein Monarch-1 with heat shock proteins. Further analysis indicates that analogous to plant R proteins, Hsp90 is required for Monarch-1 activity. In human monocytes, Monarch-1 associates with Hsp90, and these complexes are sensitive to treatment with specific Hsp90 inhibitors. Disruption of these complexes results in rapid degradation of Monarch-1 via the proteasome and prevents Monarch-1-induced proteolysis of NF-kappaB-inducing kinase. This demonstrates that Hsp90 is a critical regulator of Monarch-1 anti-inflammatory activity.

• Authors: Janelle C Arthur, John D Lich, Ramy K Aziz, Malak Kotb, Jenny P-Y Ting
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 9 Pg. 6291-6 (Nov 01 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17947705 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• HSP70 Heat-Shock Proteins
• HSP90 Heat-Shock Proteins
• Intracellular Signaling Peptides and Proteins
• NLRP12 protein, human
• Protein Serine-Threonine Kinases
• NF-kappa B kinase
• Proteasome Endopeptidase Complex

Topics

• Cells, Cultured
• HSP70 Heat-Shock Proteins (chemistry, metabolism)
• HSP90 Heat-Shock Proteins (metabolism)
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Monocytes (metabolism)
• Proteasome Endopeptidase Complex (metabolism)
• Protein Binding
• Protein Serine-Threonine Kinases (metabolism)
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization