Hsp90 regulates processing of NF-κB2 p100 involving protection of NF-κB-inducing kinase (NIK) from autophagy-mediated degradation

NF-κB-inducing kinase （NIK） is required for NF-κB activation based on the processing of NF-κB p100. Here we report a novel mechanism of NIK regulation involving the chaperone 90 kDa heat shock protein （Hsp90） and autophagy. Functional inhibition of lisp90 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 α subunit of IκB3 kinase to p 100, a key step in induction of p100 processing. These findings define an alternative mechanism for Hsp90 client degradation and identify a novel function ofautophagy in NF-κB regulation. These findings also suggest a new therapeutic strategy for diseases associated with p 100 processing.