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: Zhao Zhang, Yanyan Wang, Chuanchuan Li, Zhubing Shi, Qian Hao, Wenjia Wang, Xiaomin Song, Yun Zhao, Shi Jiao, Zhaocai Zhou
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 32 Pg. 19558-68 (Aug 07 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26112410 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Adaptor Proteins, Vesicular Transport
• Intracellular Signaling Peptides and Proteins
• KPNB1 protein, human
• Lipopolysaccharides
• N2,N4-dibenzylquinazoline-2,4-diamine
• NF-kappa B p52 Subunit
• NPLOC4 protein, human
• Nuclear Proteins
• Proteins
• Quinazolines
• UFD1 protein, human
• beta Karyopherins
• SKP Cullin F-Box Protein Ligases
• Proteasome Endopeptidase Complex

Topics

• Adaptor Proteins, Vesicular Transport
• Animals
• Cell Line, Tumor
• Endoplasmic Reticulum (drug effects, metabolism)
• Fibroblasts (cytology, drug effects, metabolism)
• Gene Expression Regulation
• HEK293 Cells
• Humans
• Intracellular Signaling Peptides and Proteins
• Lipopolysaccharides
• Lung (drug effects, metabolism, pathology)
• Lymphocytes (drug effects, metabolism, pathology)
• Male
• Mice
• Mice, Knockout
• NF-kappa B p52 Subunit (genetics, metabolism)
• Nuclear Proteins (genetics, metabolism)
• Pneumonia (chemically induced, genetics, metabolism, pathology)
• Proteasome Endopeptidase Complex (drug effects, metabolism)
• Proteins (genetics, metabolism)
• Proteolysis (drug effects)
• Quinazolines (pharmacology)
• SKP Cullin F-Box Protein Ligases (genetics, metabolism)
• Signal Transduction
• Transcription, Genetic
• Ubiquitination
• beta Karyopherins (antagonists & inhibitors, genetics, metabolism)