| Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IκB kinase （IKK） |
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| 引用本文： | Qing G,Yan P,Xiao G. Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IκB kinase （IKK）[J]. Cell research, 2006, 16(11): 895-901 |
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| 作者姓名： | Qing G Yan P Xiao G |
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| 作者单位： | Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ08854, USA |
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| 基金项目： | Acknowledgments We thank Drs Covey L for the Ramos cells, Mizushima N for Atg5 null MEFs and 0zer HL for ts20 cells. This study was assisted partially by research grants from the New Jersey Commission on Cancer Research, Fifth District AHEPA Cancer Research Foundation, American Cancer Society RSG MG0-110116 and National Institutions of Health 1 R01 CA 116616 to GX. |
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| 摘 要： | Autophagic and proteasomal proteolysis are two major pathways for degradation of cellular constituents. Current models suggest that autophagy is responsible for the nonselective bulk degradation of long-lived proteins and organelles while the proteasome specifically degrades short-lived proteins including misfolded proteins caused by the absence of Hsp90 function. Here, we show that the IκB kinase （IKK）, an essential activator of NF-κB, is selectively degraded by autophagy when Hsp90 is inhibited by geldanamycin （GA）, a specific Hsp90 inhibitor showing highly effective anti-tumor activity. We find that in this case inactivation of ubiquitination or proteasome fails to block IKK degradation. However, inhibition of autophagy by an autophagy inhibitor or knockout of Atg5, a key component of the autophagy pathway, significantly rescues IKK from GA-induced degradation. These findings provide the first evidence that an Hsp90 client may be degraded by a mechanism different from the proteasome pathway and establish a molecular link among Hsp90, NF-κB and autophagy
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| 关 键 词： | 自我吞噬 激酶 格尔德霉素 细胞老化 |
| 收稿时间： | 2006-09-28 |
| 修稿时间： | 2006-09-282006-10-10 |
Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IkappaB kinase (IKK) |
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| Qing Guoliang,Yan Pengrong,Xiao Gutian. Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IkappaB kinase (IKK)[J]. Cell research, 2006, 16(11): 895-901 |
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| Authors: | Qing Guoliang Yan Pengrong Xiao Gutian |
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| Affiliation: | Guoliang Qing~1 Pengrong Yan~1 Gutian Xiao ~1Department of Cell Biology and Neuroscience,Rutgers,The State University of New Jersey,604 Allison Road,Piscataway,08854,USA |
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| Abstract: | Autophagic and proteasomal proteolysis are two major pathways for degradation of cellular constituents. Current models suggest that autophagy is responsible for the nonselective bulk degradation of long-lived proteins and organelles while the proteasome specifically degrades short-lived proteins including misfolded proteins caused by the absence of Hsp90 function. Here, we show that the IkappaB kinase (IKK), an essential activator of NF-kappaB, is selectively degraded by autophagy when Hsp90 is inhibited by geldanamycin (GA), a specific Hsp90 inhibitor showing highly effective anti-tumor activity. We find that in this case inactivation of ubiquitination or proteasome fails to block IKK degradation. However, inhibition of autophagy by an autophagy inhibitor or knockout of Atg5, a key component of the autophagy pathway, significantly rescues IKK from GA-induced degradation. These findings provide the first evidence that an Hsp90 client may be degraded by a mechanism different from the proteasome pathway and establish a molecular link among Hsp90, NF-kappaB and autophagy. |
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