The Schizophrenia-Related Protein Dysbindin-1A Is Degraded and Facilitates NF-Kappa B Activity in the Nucleus

Cheng Fu; Dong Chen; Ruijie Chen; Qingsong Hu; Guanghui Wang

doi:10.1371/journal.pone.0132639

The Schizophrenia-Related Protein Dysbindin-1A Is Degraded and Facilitates NF-Kappa B Activity in the Nucleus

PLoS One. 2015 Jul 14;10(7):e0132639. doi: 10.1371/journal.pone.0132639. eCollection 2015.

Authors

Cheng Fu¹, Dong Chen², Ruijie Chen³, Qingsong Hu², Guanghui Wang⁴

Affiliations

¹ Laboratory of Molecular Neuropathology, Key Laboratory of Brain Function and Diseases and School of Life Sciences, University of Science and Technology of China, Chinese Academy of Sciences. Hefei, Anhui, China.
² Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
³ Department of Clinical Pharmacy and Pharmacology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
⁴ Laboratory of Molecular Neuropathology, Key Laboratory of Brain Function and Diseases and School of Life Sciences, University of Science and Technology of China, Chinese Academy of Sciences. Hefei, Anhui, China; Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.

Abstract

Dystrobrevin-binding protein 1 (DTNBP1), a gene encoding dysbindin-1, has been identified as a susceptibility gene for schizophrenia. Functioning with partners in synapses or the cytoplasm, this gene regulates neurite outgrowth and neurotransmitter release. Loss of dysbindin-1 affects schizophrenia pathology. Dysbindin-1 is also found in the nucleus, however, the characteristics of dysbindin in the nucleus are not fully understood. Here, we found that dysbindin-1A is degraded in the nucleus via the ubiquitin-proteasome system and that amino acids 2-41 at the N-terminus are required for this process. By interacting with p65, dysbindin-1A promotes the transcriptional activity of NF-kappa B in the nucleus and positively regulates MMP-9 expression. Taken together, the data obtained in this study demonstrate that dysbindin-1A protein levels are highly regulated in the nucleus and that dysbindin-1A regulates transcription factor NF-kappa B activity to promote the expression of MMP-9 and TNF-α.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Nucleus / metabolism*
Dysbindin
Dystrophin-Associated Proteins / chemistry
Dystrophin-Associated Proteins / metabolism*
Gene Expression Regulation, Enzymologic
HEK293 Cells
Humans
Matrix Metalloproteinase 9 / genetics
NF-kappa B / genetics
NF-kappa B / metabolism*
Proteasome Endopeptidase Complex / metabolism
Proteolysis*
Schizophrenia / metabolism*
Transcription, Genetic
Tumor Necrosis Factor-alpha / genetics
Ubiquitin / metabolism

Substances

DTNBP1 protein, human
Dysbindin
Dystrophin-Associated Proteins
NF-kappa B
Tumor Necrosis Factor-alpha
Ubiquitin
Matrix Metalloproteinase 9
Proteasome Endopeptidase Complex

Grants and funding

The National High-tech Research and Development program of China 973-projects (2012CB947602, http://www.most.gov.cn/), the National Natural Sciences Foundation of China (Nos. 31330030 and 81371393, http://www.nsfc.gov.cn/) and Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases (BM2013003, http://www.jstd.gov.cn/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.