ASK1 negatively regulates the 26 S proteasome.

The 26 S proteasome, composed of the 20 S core and 19 S regulatory particle, plays a central role in ubiquitin-dependent proteolysis. Disruption of this process contributes to the pathogenesis of the various diseases; however, the mechanisms underlying the regulation of 26 S proteasome activity remain elusive. Here, cell culture ...
experiments and in vitro assays demonstrated that apoptosis signal-regulating kinase 1 (ASK1), a member of the MAPK kinase kinase family, negatively regulated 26 S proteasome activity. Immunoprecipitation/Western blot analyses revealed that ASK1 did not interact with 20 S catalytic core but did interact with ATPases making up the 19 S particle, which is responsible for recognizing polyubiquitinated proteins, unfolding them, and translocating them into the 20 S catalytic core in an ATP-dependent process. Importantly, ASK1 phosphorylated Rpt5, an AAA ATPase of the 19 S proteasome, and inhibited its ATPase activity, an effect that may underlie the ability of ASK1 to inhibit 26 S proteasome activity. The current findings point to a novel role for ASK1 in the regulation of 26 S proteasome and offer new strategies for treating human diseases caused by proteasome malfunction.
Mesh Terms:
Animals, Blotting, Western, Cells, Cultured, Embryo, Mammalian, Fibroblasts, Glioma, HeLa Cells, Humans, Immunoprecipitation, Kidney, MAP Kinase Kinase Kinase 5, Mice, Mice, Knockout, Neuroblastoma, Proteasome Endopeptidase Complex, Protein Subunits, RNA, Messenger, RNA, Small Interfering, Rats, Reverse Transcriptase Polymerase Chain Reaction, Ubiquitination
J. Biol. Chem.
Date: Nov. 19, 2010
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