Amino acid analogs activate NF-κB through redox-dependent IκB-α degradation by the proteasome without apparent IκB-α phosphorylation -: Consequence on HIV-1 long terminal repeat activation

We report here that amino acid analogs, which activate hsp70 promoter, are powerful transcriptional activators of human immunodeficiency virus 1 (HIV-1) long terminal repeat (LTR), an activation which was impaired when the two kappa B sites present in the LTR were mutated or deleted. Amino acid analogs also stimulated the transcription of a kappa B-controlled reporter gene. Upon treatment with amino acid analogs, the two NF-kappa B subunits (p65 and p50), which are characterized by a relatively long half-life, redistributed into the nucleus where they bound to kappa B elements. This phenomenon, which began to be detectable after 1 h of treatment, was concomitant with the degradation of the short lived inhibitory subunit I kappa B-alpha by the proteasome. However, contrasting with other NF-kappa B inducers that trigger I kappa B-alpha degradation through a phosphorylation step, amino acid analogs did not change I kappa B-alpha isoform composition. Antioxidant conditions inhibited amino acid analog stimulatory action toward NF-kappa B. This suggests that aberrant protein conformation probably generates a prooxidant state that is necessary for I kappa B-alpha proteolysis by the proteasome. Moreover, this activation of NF-kappa B appeared different from that mediated by endoplasmic reticulum overload as it was not inhibited by calcium chelation.