Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 36434-36446 |
| Number of pages | 13 |
| Journal | Journal of Biological Chemistry |
| Volume | 285 |
| Issue number | 47 |
| DOIs | |
| Publication status | Published - 2010 Nov 19 |
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All Science Journal Classification (ASJC) codes
- Biochemistry
- Cell Biology
- Molecular Biology
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ASK1 negatively regulates the 26 S proteasome. / Ji, Won Um; Eunju, Im; Joongkyu, Park; Yohan, Oh; Boram, Min; Hyun, Jung Lee; Jong, Bok Yoon; Chung, Kwang Chul.
In: Journal of Biological Chemistry, Vol. 285, No. 47, 19.11.2010, p. 36434-36446.Research output: Contribution to journal › Article
TY - JOUR
T1 - ASK1 negatively regulates the 26 S proteasome
AU - Ji, Won Um
AU - Eunju, Im
AU - Joongkyu, Park
AU - Yohan, Oh
AU - Boram, Min
AU - Hyun, Jung Lee
AU - Jong, Bok Yoon
AU - Chung, Kwang Chul
PY - 2010/11/19
Y1 - 2010/11/19
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=78449252451&partnerID=8YFLogxK
U2 - 10.1074/jbc.M110.133777
DO - 10.1074/jbc.M110.133777
M3 - Article
VL - 285
SP - 36434
EP - 36446
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 47
ER -