The Molecular Chaperone HSP70 Binds to and Stabilizes NOD2, an Important Protein Involved in Crohn Disease

Abstract

Background: NOD2, an innate immune receptor, senses bacterial cell wall fragments. NOD2 mutations are linked to Crohn disease. Results: HSP70 enhances NOD2's activity and increases its half-life. Conclusion: NOD2 mutants are less stable than the wild type. HSP70 overexpression stabilizes the NOD2 Crohn mutants and rescues its activity. Significance: Stabilization of the NOD2 mutants may provide an effective therapy for Crohn disease.

The effect of NOD2 on the microbiota in Crohn's disease

“…Chaperone proteins improve the stability of proteins by enhancing folding energetics [44]. NOD2 recruits the chaperone proteins heat-shock protein 70 (HSP70) and heat-shock protein 90 to confer stability and dissociation from either result in increased degradation [10,45]. …”

“…Interestingly, by overexpressing HSP70, the NOD2 CD mutants have restored stability and correct inflammatory responses [10]. Interactions between HSP70 and NOD2 are critical for proper function as there are also CD mutations of HSP70 [46].…”

“…Defensin-based therapeutics could compensate for the decreased expression of the necessary anti-microbial peptides without eliminating commensal bacteria [9]. Recent efforts have demonstrated that the NOD2 mutants are unstable, and by enhancing their half-life through interactions with a chaperone protein, appropriate signaling was restored [10]. Use of a pharmacological chaperone to mimic this heightened function has the potential to directly target all mis-signaling events of NOD2 mutants.…”

International Union of Basic and Clinical Pharmacology. XCVI. Pattern Recognition Receptors in Health and Disease

“…Both NOD1 and NOD2 are known to associate with cellular chaperones such as SGT1 (suppressor of G2 allele of Skp1), HSP70 and HSP90, which are hypothesized to play an important role in maintaining the receptors in an inactive form and to contribute to protein stability (da Silva Correia et al, 2007;Mayor et al, 2007;Lee et al, 2012c;Mohanan and Grimes, 2014). In a process dependent upon ATP binding and hydrolysis, NOD1 and NOD2 adopt an open conformation, most likely displacing the bound chaperones, undergo NBD-mediated oligomerization, and make their CARD available for interaction with downstream signaling adaptors.…”

Crohn’s Disease Variants of Nod2 Are Stabilized by the Critical Contact Region of Hsp70

“…We have previously shown that the chaperone protein, heat shock protein 70 (Hsp70), binds and stabilizes Nod2 12 . Hsp70 is responsible for a diverse range of functions, which when bound to the client protein aids the protein in adopting a more stable conformation, protects vulnerable regions from disruptive interactions, or inhibits self-aggregation 13–14 .…”