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Heat Shock Protein 90 Associates with Monarch-1 and Regulates Its Ability to Promote Degradation of NF-B-Inducing Kinase¹

Janelle C. Arthur^2,*,, John D. Lich^2,*,, Ramy K. Aziz, Malak Kotb and Jenny P.-Y. Ting^3,*,

^* Department of Microbiology and Immunology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599; Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, Egypt; and Departments of Molecular Sciences and Surgery, University of Tennessee Health Science Center, Memphis, TN 38104

Monarch-1/NLRP12 is expressed in myeloid cells and functions as a negative regulator of inflammation by inducing proteasome-mediated degradation of NF-B-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-B-inducing kinase. This demonstrates that Hsp90 is a critical regulator of Monarch-1 anti-inflammatory activity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI063031, DE016326, DK38108, SERCEB A1-02-031, and a Sandler Program in Asthma Research Senior Investigator Award (to J.P,-Y.T.). J.D.L. was supported by The American Cancer Society. J.C.A. was supported by National Institutes of Health Training Grant T32-A1007273-22.

² J.C.A. and J.D.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Jenny Pan-Yun Ting, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599. E-mail address: panyun{at}med.unc.edu

⁴ Abbreviations used in this paper: NLR, nucleotide-binding domain leucine-rich repeat; R protein, disease-resistance protein; Hsp, heat shock protein; NIK, NF-B-inducing kinase; Ha, hemagglutinin; Hsc, heat shock cognate; 2D, two dimensional; MS, mass spectometry; GA, geldanamycin; TAK1, TGF--activated kinase 1; LRR, leucine-rich repeat; NACHT, NAIP, CIITA, HET-E, and TP1 domain; NALP3, NACHT-, LRR-, and PYD-containing protein.