The Transitional Endoplasmic Reticulum ATPase p97 Regulates the Alternative Nuclear Factor NF-kappa B Signaling via Partial Degradation of the NF-kappa B Subunit p100

doi:10.1074/jbc.M114.630061

	The Transitional Endoplasmic Reticulum ATPase p97 Regulates the Alternative Nuclear Factor NF-kappa B Signaling via Partial Degradation of the NF-kappa B Subunit p100
	Zhang, Zhao 1; Wang, Yanyan 1; Li, Chuanchuan 1; Shi, Zhubing 1,2; Hao, Qian 1; Wang, Wenjia 1; Song, Xiaomin 1; Zhao, Yun 1; Jiao, Shi 1; Zhou, Zhaocai1,3
	2015-08-07
发表期刊	JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN	0021-9258
卷号	290 期号:32 页码:19558-19568
发表状态	已发表
DOI	10.1074/jbc.M114.630061
摘要	Partial degradation of the p100 subunit to generate p52 subunit is a hallmark of the alternative NF-kappa B pathway, which has been implicated in cancer. Here, we uncovered a role of the p97-Npl4-Ufd1 complex in mediating p100-to-p52 processing and therefore positively regulating the alternative NF-kappa B pathway. We observed an elevation of p97 mRNA levels in lymphoma patients, which positively correlates with NFKB2 expression, a downstream target gene of the alternative NF-kappa B pathway. Moreover, NFKB2 mRNA levels were aberrantly down-regulated in patients with inclusion body myopathy associated with Paget's disease of the bone and frontotemporal dementia (IBMPFD), a disease caused by mutation of p97. Inactivation of p97 or depletion of the p97-Npl4-Ufd1 complex inhibits the processing of p100 into p52, decreasing transcription of the downstream target genes. Further analyses reveal that the p97-Npl4-Ufd1 complex interacts with F-box and WD repeats protein SCF beta TrCP complex to regulate the partial degradation of p100, a process involving K48- and K11-linked ubiquitination. In line with this, in LPS-induced lung damage mice model, generation of p52 is significantly decreased in p97-KD mice compared with mock mice. Finally, abrogation of p97 ATPase activity by its specific inhibitor DBeQ, efficiently decreased proliferation of lymphoma cells. Collectively, our study revealed a regulatory role of the p97-Npl4-Ufd1 complex in regulating p100 partial degradation, highlighting the potential of p97 as a drug target for cancers with aberrant activation of the alternative NF-kappa B pathway.
收录类别	SCI ; EI
语种	英语
资助项目	Knowledge Innovation Program of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences[2014KIP202]
WOS研究方向	Biochemistry & Molecular Biology
WOS类目	Biochemistry & Molecular Biology
WOS记录号	WOS:000359364600019
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
EI入藏号	20153301178034
EI主题词	Cell membranes ; Diseases ; Genes ; Mammals ; Oncology ; Transcription
EI分类号	Bioengineering and Biology:461 ; Agricultural Equipment and Methods; Vegetation and Pest Control:821
WOS关键词	CONTAINING PROTEIN P97 ; INCLUSION-BODY MYOPATHY ; FRONTOTEMPORAL DEMENTIA ; EXPRESSION LEVEL ; NF-KAPPA-B2 P100 ; GENE-EXPRESSION ; UBIQUITIN ; LYMPHOMA ; PATHWAY ; KINASE
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/2156
专题	生命科学与技术学院_特聘教授组_周兆才组
通讯作者	Jiao, Shi
作者单位	1.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai, Shanghai 200031, Peoples R China 2.Tongji Univ, Sch Life Sci & Technol, Shanghai 200092, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Zhao,Wang, Yanyan,Li, Chuanchuan,et al. The Transitional Endoplasmic Reticulum ATPase p97 Regulates the Alternative Nuclear Factor NF-kappa B Signaling via Partial Degradation of the NF-kappa B Subunit p100[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2015,290(32):19558-19568.
APA	Zhang, Zhao.,Wang, Yanyan.,Li, Chuanchuan.,Shi, Zhubing.,Hao, Qian.,...&Zhou, Zhaocai.(2015).The Transitional Endoplasmic Reticulum ATPase p97 Regulates the Alternative Nuclear Factor NF-kappa B Signaling via Partial Degradation of the NF-kappa B Subunit p100.JOURNAL OF BIOLOGICAL CHEMISTRY,290(32),19558-19568.
MLA	Zhang, Zhao,et al."The Transitional Endoplasmic Reticulum ATPase p97 Regulates the Alternative Nuclear Factor NF-kappa B Signaling via Partial Degradation of the NF-kappa B Subunit p100".JOURNAL OF BIOLOGICAL CHEMISTRY 290.32(2015):19558-19568.