The Transitional Endoplasmic Reticulum ATPase p97 Regulates the Alternative Nuclear Factor NF-κB Signaling via Partial Degradation of the NF-κB Subunit p100.
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.
Mesh Terms:
Animals, Cell Line, Tumor, Endoplasmic Reticulum, Fibroblasts, Gene Expression Regulation, HEK293 Cells, Humans, Lipopolysaccharides, Lung, Lymphocytes, Male, Mice, Mice, Knockout, NF-kappa B p52 Subunit, Nuclear Proteins, Pneumonia, Proteasome Endopeptidase Complex, Proteins, Proteolysis, Quinazolines, SKP Cullin F-Box Protein Ligases, Signal Transduction, Transcription, Genetic, Ubiquitination, beta Karyopherins
Animals, Cell Line, Tumor, Endoplasmic Reticulum, Fibroblasts, Gene Expression Regulation, HEK293 Cells, Humans, Lipopolysaccharides, Lung, Lymphocytes, Male, Mice, Mice, Knockout, NF-kappa B p52 Subunit, Nuclear Proteins, Pneumonia, Proteasome Endopeptidase Complex, Proteins, Proteolysis, Quinazolines, SKP Cullin F-Box Protein Ligases, Signal Transduction, Transcription, Genetic, Ubiquitination, beta Karyopherins
J. Biol. Chem.
Date: Aug. 07, 2015
PubMed ID: 26112410
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