Hsp90 Regulates Processing Of Nf-Kappa B2 P100 Involving Protection Of Nf-Kappa B-Inducing Kinase (Nik) From Autophagy-Mediated Degradation

NF-kappa B-inducing kinase (NIK) is required for NF-kappa B activation based on the processing of NF-kappa B2 p 100. Here we report a novel mechanism of NIK regulation involving the chaperone 90 kDa heat shock protein (Hsp90) and autophagy. Functional inhibition of Hsp90 by the anti-tumor agent geldanamycin (GA) efficiently disrupts its interaction with NIK, resulting in NIK degradation and subsequent blockage of p100 processing. Surprisingly, GA-induced NIK degradation is mediated by autophagy, but largely independent of the ubiquitin-proteasome system. Hsp90 seems to be specifically involved in the folding/stabilization of NIK protein, because GA inhibition does not affect NIK mRNA transcription and translation. Furthermore, Hsp90 is not required for NIK-mediated recruitment of the a subunit of I kappa B kinase to p100, a key step in induction of p100 processing. These findings define an alternative mechanism for Hsp90 client degradation and identify a novel function of autophagy in NF-kappa B regulation. These findings also suggest a new therapeutic strategy for diseases associated with p100 processing.