title: The Transitional Endoplasmic Reticulum ATPase p97 Regulates the Alternative Nuclear Factor NF-κB Signaling via Partial Degradation of the NF-κB Subunit p100.
abstract: Partial degradation of the p100 subunit to generate p52 subunit is a hallmark of the alternative NF-κB 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-κB 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-κB 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(βTrCP) 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-κB pathway.
authors.affiliation: From the National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: From the National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Chuanchuan
authors.initials: C
authors.lastname: Li
authors.affiliation: From the National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China, and.
authors.forename: Zhubing
authors.initials: Z
authors.lastname: Shi
authors.affiliation: From the National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Hao
authors.affiliation: From the National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Wenjia
authors.initials: W
authors.lastname: Wang
authors.affiliation: From the National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Song
authors.affiliation: From the National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: From the National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, jiaoshi@sibcb.ac.cn.
authors.forename: Shi
authors.initials: S
authors.lastname: Jiao
authors.affiliation: From the National Center for Protein Science Shanghai, State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China zczhou@sibcb.ac.cn.
authors.forename: Zhaocai
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D054875:Ubiquitination; D028961:beta Karyopherins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D047908:Intracellular Signaling Peptides and Proteins; C424166:KPNB1 protein, human; D008070:Lipopolysaccharides; C558357:N2,N4-dibenzylquinazoline-2,4-diamine; D052003:NF-kappa B p52 Subunit; C514112:NPLOC4 protein, human; D009687:Nuclear Proteins; D011506:Proteins; D011799:Quinazolines; C491497:UFD1 protein, human; D028961:beta Karyopherins; D044843:SKP Cullin F-Box Protein Ligases; D046988:Proteasome Endopeptidase Complex
keywords: NF-κB (NF-κB); cell signaling; lymphoma; p97-Npl4-Ufd1 complex; protein degradation; ubiquitylation (ubiquitination)