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学科主题: 基础医学
题名:
Human Surfactant Protein A2 Gene Mutations Impair Dimmer/Trimer Assembly Leading to Deficiency in Protein Sialylation and Secretion
作者: Song, Yi5; Fang, Guodong5; Shen, Haitao5; Li, Hui5; Yang, Wenbing5; Pan, Bing1,2,3; Huang, Guowei5; Lin, Guangyu6,7; Ma, Lian6,7; Willard, Belinda4; Gu, Jiang5; Zheng, Lemin1,2,3; Wang, Yongyu5
刊名: PLOS ONE
发表日期: 2012-10-03
DOI: 10.1371/journal.pone.0046559
卷: 7, 期:10
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Multidisciplinary Sciences
研究领域[WOS]: Science & Technology - Other Topics
关键词[WOS]: ENDOPLASMIC-RETICULUM STRESS ; PRIMARY TRANSLATION PRODUCTS ; BRONCHOALVEOLAR LAVAGE ; PULMONARY-FIBROSIS ; GLYCOPROTEIN-A ; DEGRADATION ; DOMAIN ; DISEASE ; LUNG ; GLYCOSYLATION
英文摘要:

Surfactant protein A2 (SP-A2) plays an essential role in surfactant metabolism and lung host defense. SP-A2 mutations in the carbohydrate recognition domain have been related to familial pulmonary fibrosis and can lead to a recombinant protein secretion deficiency in vitro. In this study, we explored the molecular mechanism of protein secretion deficiency and the subsequent biological effects in CHO-K1 cells expressing both wild-type and several different mutant forms of SP-A2. We demonstrate that the SP-A2 G231V and F198S mutants impair the formation of dimmer/trimer SP-A2 which contributes to the protein secretion defect. A deficiency in sialylation, but not N-linked glycosylation, is critical to the observed dimmer/trimer impairment-induced secretion defect. Furthermore, both mutant forms accumulate in the ER and form NP-40-insoluble aggregates. In addition, the soluble mutant SP-A2 could be partially degraded through the proteasome pathway but not the lysosome or autophagy pathway. Intriguingly, 4-phenylbutyrate acid (4-PBA), a chemical chaperone, alleviates aggregate formation and partially rescued the protein secretion of SP-A2 mutants. In conclusion, SP-A2 G231V and F198S mutants impair the dimmer/trimer assembly, which contributes to the protein sialylation and secretion deficiency. The intracellular protein mutants could be partially degraded through the proteasome pathway and also formed aggregates. The treatment of the cells with 4-PBA resulted in reduced aggregation and rescued the secretion of mutant SP-A2.

语种: 英语
所属项目编号: 210159 ; 2010CB912504 ; 2011CB503900 ; 30900595 ; 81170101
项目资助者: Key Project of Chinese Ministry of Education ; Introduction of Talents Program of Institutions of Higher Education of Guangdong Province ; "973&prime ; &prime ; National ST Major Project ; National Natural Science Foundation of China
WOS记录号: WOS:000309454000055
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/59509
Appears in Collections:基础医学院_心血管所_期刊论文

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作者单位: 1.Cleveland Clin, Prote Lab, Cleveland, OH 44106 USA
2.Shantou Univ Med Coll, Dept Pathol, Shantou, Guangdong, Peoples R China
3.Peking Univ Hlth Sci Ctr, Key Lab Mol Cardiovasc Sci, Educ Minist, Inst Cardiovasc Sci,Sch Basic Med Sci, Beijing, Peoples R China
4.Peking Univ Hlth Sci Ctr, Key Lab Mol Cardiovasc Sci, Educ Minist, Inst Syst Biomed,Sch Basic Med Sci, Beijing, Peoples R China
5.Minist Hlth, Key Lab Cardiovasc Mol Biol & Regulatory Peptides, Beijing, Peoples R China
6.Shantou Univ Med Coll, Affiliated Hosp 2, Dept Pediat, Shantou, Guangdong, Peoples R China
7.Shantou Univ Med Coll, Affiliated Hosp 2, Translat Med Ctr, Shantou, Guangdong, Peoples R China

Recommended Citation:
Song, Yi,Fang, Guodong,Shen, Haitao,et al. Human Surfactant Protein A2 Gene Mutations Impair Dimmer/Trimer Assembly Leading to Deficiency in Protein Sialylation and Secretion[J]. PLOS ONE,2012,7(10).
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