Role of the CCAAT-binding protein NFY in SCA17 pathogenesis.
Spinocerebellar ataxia 17 (SCA17) is caused by expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) that is ubiquitously expressed in both central nervous system and peripheral tissues. The spectrum of SCA17 clinical presentation is broad. The precise pathogenic mecha...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3328435?pdf=render |
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| author | Li-Ching Lee Chiung-Mei Chen Hao-Chun Wang Hsiao-Han Hsieh I-Sheng Chiu Ming-Tsan Su Hsiu-Mei Hsieh-Li Chung-Hsin Wu Guan-Chiun Lee Guey-Jen Lee-Chen Jung-Yaw Lin |
| author_facet | Li-Ching Lee Chiung-Mei Chen Hao-Chun Wang Hsiao-Han Hsieh I-Sheng Chiu Ming-Tsan Su Hsiu-Mei Hsieh-Li Chung-Hsin Wu Guan-Chiun Lee Guey-Jen Lee-Chen Jung-Yaw Lin |
| author_sort | Li-Ching Lee |
| collection | DOAJ |
| description | Spinocerebellar ataxia 17 (SCA17) is caused by expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) that is ubiquitously expressed in both central nervous system and peripheral tissues. The spectrum of SCA17 clinical presentation is broad. The precise pathogenic mechanism in SCA17 remains unclear. Previously proteomics study using a cellular model of SCA17 has revealed reduced expression of heat shock 70 kDa protein 5 (HSPA5) and heat shock 70 kDa protein 8 (HSPA8), suggesting that impaired protein folding may contribute to the cell dysfunction of SCA17 (Lee et al., 2009). In lymphoblastoid cells, HSPA5 and HSPA8 expression levels in cells with mutant TBP were also significantly lower than that of the control cells (Chen et al., 2010). As nuclear transcription factor Y (NFY) has been reported to regulate HSPA5 transcription, we focused on if NFY activity and HSPA5 expression in SCA17 cells are altered. Here, we show that TBP interacts with NFY subunit A (NFYA) in HEK-293 cells and NFYA incorporated into mutant TBP aggregates. In both HEK-293 and SH-SY5Y cells expressing TBP/Q(61~79), the level of soluble NFYA was significantly reduced. In vitro binding assay revealed that the interaction between TBP and NFYA is direct. HSPA5 luciferase reporter assay and endogenous HSPA5 expression analysis in NFYA cDNA and siRNA transfection cells further clarified the important role of NFYA in regulating HSPA5 transcription. In SCA17 cells, HSPA5 promoter activity was activated as a compensatory response before aggregate formation. NFYA dysfunction was indicated in SCA17 cells as HSPA5 promoter activity reduced along with TBP aggregate formation. Because essential roles of HSPA5 in protection from neuronal apoptosis have been shown in a mouse model, NFYA could be a target of mutant TBP in SCA17. |
| first_indexed | 2024-04-14T08:14:30Z |
| format | Article |
| id | doaj.art-9c8b513e7652499da69408c1cae0f26b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-14T08:14:30Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-9c8b513e7652499da69408c1cae0f26b2022-12-22T02:04:27ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-0174e3530210.1371/journal.pone.0035302Role of the CCAAT-binding protein NFY in SCA17 pathogenesis.Li-Ching LeeChiung-Mei ChenHao-Chun WangHsiao-Han HsiehI-Sheng ChiuMing-Tsan SuHsiu-Mei Hsieh-LiChung-Hsin WuGuan-Chiun LeeGuey-Jen Lee-ChenJung-Yaw LinSpinocerebellar ataxia 17 (SCA17) is caused by expansion of the polyglutamine (polyQ) tract in human TATA-box binding protein (TBP) that is ubiquitously expressed in both central nervous system and peripheral tissues. The spectrum of SCA17 clinical presentation is broad. The precise pathogenic mechanism in SCA17 remains unclear. Previously proteomics study using a cellular model of SCA17 has revealed reduced expression of heat shock 70 kDa protein 5 (HSPA5) and heat shock 70 kDa protein 8 (HSPA8), suggesting that impaired protein folding may contribute to the cell dysfunction of SCA17 (Lee et al., 2009). In lymphoblastoid cells, HSPA5 and HSPA8 expression levels in cells with mutant TBP were also significantly lower than that of the control cells (Chen et al., 2010). As nuclear transcription factor Y (NFY) has been reported to regulate HSPA5 transcription, we focused on if NFY activity and HSPA5 expression in SCA17 cells are altered. Here, we show that TBP interacts with NFY subunit A (NFYA) in HEK-293 cells and NFYA incorporated into mutant TBP aggregates. In both HEK-293 and SH-SY5Y cells expressing TBP/Q(61~79), the level of soluble NFYA was significantly reduced. In vitro binding assay revealed that the interaction between TBP and NFYA is direct. HSPA5 luciferase reporter assay and endogenous HSPA5 expression analysis in NFYA cDNA and siRNA transfection cells further clarified the important role of NFYA in regulating HSPA5 transcription. In SCA17 cells, HSPA5 promoter activity was activated as a compensatory response before aggregate formation. NFYA dysfunction was indicated in SCA17 cells as HSPA5 promoter activity reduced along with TBP aggregate formation. Because essential roles of HSPA5 in protection from neuronal apoptosis have been shown in a mouse model, NFYA could be a target of mutant TBP in SCA17.http://europepmc.org/articles/PMC3328435?pdf=render |
| spellingShingle | Li-Ching Lee Chiung-Mei Chen Hao-Chun Wang Hsiao-Han Hsieh I-Sheng Chiu Ming-Tsan Su Hsiu-Mei Hsieh-Li Chung-Hsin Wu Guan-Chiun Lee Guey-Jen Lee-Chen Jung-Yaw Lin Role of the CCAAT-binding protein NFY in SCA17 pathogenesis. PLoS ONE |
| title | Role of the CCAAT-binding protein NFY in SCA17 pathogenesis. |
| title_full | Role of the CCAAT-binding protein NFY in SCA17 pathogenesis. |
| title_fullStr | Role of the CCAAT-binding protein NFY in SCA17 pathogenesis. |
| title_full_unstemmed | Role of the CCAAT-binding protein NFY in SCA17 pathogenesis. |
| title_short | Role of the CCAAT-binding protein NFY in SCA17 pathogenesis. |
| title_sort | role of the ccaat binding protein nfy in sca17 pathogenesis |
| url | http://europepmc.org/articles/PMC3328435?pdf=render |
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