Hsp90 regulates processing of NF-kappa B2 p100 involving protection of NF-kappa B-inducing kinase (NIK) from autophagy-mediated degradation.
NF-kappaB-inducing kinase (NIK) is required for NF-kappaB activation based on the processing of NF-kappaB2 p100. 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 alpha subunit of IkappaB 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-kappaB regulation. These findings also suggest a new therapeutic strategy for diseases associated with p100 processing.
Qing
Guoliang
G
Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Yan
Pengrong
P
Qu
Zhaoxia
Z
Liu
Hudan
H
Xiao
Gutian
G
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000097782:NF-kappaB-Inducing Kinase
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D052003:NF-kappa B p52 Subunit; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C001277:geldanamycin