November 2010

[JBC] Answers about ASK

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Fluorescence analysis of ubiquitinated GFP degradation in cells transfected with full-length ASK1 (WT), a kinase-inactive mutant (ASK1-KM) or a constitutive active mutant (Δ1-277-ASK1).

The 26 S proteasome plays a central role in ubiquitin-dependent protein degradation, a process vital to the cell, yet the mechanisms underlying the regulation of 26 S activity remain elusive. In this article, the authors combined cell culture and in vitro assays to demonstrate a role for the apoptosis signal-regulating kinase 1, a member of the MAPK kinase kinase family, which is activated in response to stress and apoptotic stimuli. Western blot analyses revealed that ASK1 does not interact with the 20 S catalytic core of the proteasome but does interact with ATPases in the 19 S regulatory particle, which is responsible for recognizing tagged proteins, unfolding them and translocating them into the 20 S core. The authors then found that ASK1 phosphorylates the 19 S ATPase Rpt5, inhibiting its activity and thus negatively regulating 26 S activity as a whole. These findings are the first to tie in stress kinase activation to specific effects on 26 S proteasomal function through direct phosphorylation of the proteasome complex, which may offer new strategies for treating the numerous human diseases caused by proteasome malfunction.

ASK1 Negatively Regulates the 26 S Proteasome

Ji Won Um, Eunju Im, Joongkyu Park, Yohan Oh, Boram Min, Hyun Jung Lee, Jong Bok Yoon and Kwang Chul Chung

J. Biol. Chem., published online Sept. 15, 2010


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