Analysis of the molecular mechanism ofendoplasmic reticulum-associated protein degradation (ERAD)
| Project/Area Number |
17570161
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Cell biology
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| Research Institution | Kyoto University |
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Principal Investigator |
HOSOKAWA Nobuko Institute for Frontier Medical Sciences, Kyoto University, Associate Professor, 再生医科学研究所, 助教授 (00263153)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | endoplasmic reticulum (ER) / ER-associated protein degradation (ERAD) / ER quality control (ERQC) / intracellular transport / glycoprotein / molecular chaperone / 糖タンパク質 |
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| Research Abstract |
In the present study, I analyzed the molecular mechanism of endoplasmic reticulum-associated protein degradation (ERAD), and the following points were clarified.
1.A genetic variant of α1-antitrypsin NHK is known to be degraded intracellularly by ERAD. NHK is a glycoprotein that has three N-linked oligosaccharides. I have constructed a mutant NHK-QQQ, which lacks N-glycosylation sites, and analyzed the kinetics of degradation. The following points have been clarified. (1)NHK-QQQ was degraded more rapidly than NHK. (2)NHK-QQQ was degraded by the proteasome. (3)NHK recycles between the ER and Golgi apparatus, whereas NHK-QQQ is retained in the ER.
2.We have identified a TRAP (translocon associated protein) subunit as a gene whose expression is up-regulated by ER stress. TRAP complex is composed of four subunits, and resides in the ER membrane through association with translocon, although the function of this complex is not well understood. We found that (1) the mRNA of all the four subunits of TRAP complex was up-regulated simultaneously by ER stress. (2)This induction depends on the function of Ire1, a transmembrane sensor protein for ER stress, and XBP1, a transcription factor. (3)Knock-down of one TRAP subunit by RNA interference (RNAi) decreased the expression of TRAP complex. (4)The degradation kinetics of misfolded ERAD substrates were attenuated by knock-down of the TRAP complex. Therefore, it was suggested that TRAP complex is involved in the recognition and retrotranslocation of the ERAD substrates.
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Report
(3 results)
Research Products
(19 results)
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[Journal Article] EDEM3, a soluble EDEM homolog, enhances glycoprotein endoplasmic reticulum-associated degradation and mannose trimming.2006
Author(s)
Hirao K, Natsuka Y, Tamara T, Wada I, Morito D, Natsuka S, Romero P, Sleno B, Tremblay LO, Herscovics A, Nagata K, Hosokawa N
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Journal Title
Journal of Biological Chemistry 281
Pages: 9650-9658
Related Report
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