Role of High Mobility Group Box 1 (HMGB1) in SCA17 pathogenesis

Li Ching Lee, Chiung Mei Chen, Pin Rong Wang, Ming Tsan Su, Guey Jen Lee-Chen, Chun Yen Chang

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Spinocerebellar ataxia type 17 (SCA17) involves the expression of a polyglutamine (polyQ) expanded TATA-binding protein (TBP), a general transcription initiation factor. TBP interacts with other protein factors, including high mobility group box 1 (HMGB1), to regulate gene expression. Previously, our proteomic analysis of soluble proteins prepared from mutant TBP (TBP/Q61) expressing cells revealed a reduced concentration of HMGB1. Here, we show that HMGB1 can be incorporated into mutant TBP aggregates, which leads to reduced soluble HMGB1 levels in TBP/Q61-79 expressing cells. HMGB1 overexpression reduced mutant TBP aggregation. HMGB1 cDNA and siRNA co-transfection, as well as an HSPA5 immunoblot and luciferase reporter assay demonstrated the important role of HMGB1 in the regulation of HSPA5 transcription. In starvation-stressed TBP/Q36 and TBP/Q79 cells, increased reactive oxygen species generation accelerated the cytoplasmic translocation of HMGB1, which accompanied autophagy activation. However, TBP/Q79 cells displayed a decrease in autophagy activation as a result of the reduction in the cytoplasmic HMGB1 level. In neuronal SH-SY5Y cells with induced TBP/Q61-79 expression, HMGB1 expression was reduced and accompanied by a significant reduction in the total outgrowth and branches in the TBP/Q61-79 expressing cells compared with the non-induced cells. The decreased soluble HMGB1 and impaired starvation-induced autophagy in cells suggest that HMGB1 may be a critical modulator of polyQ disease pathology and may represent a target for drug development.

Original languageEnglish
Article numbere115809
JournalPloS one
Volume9
Issue number12
DOIs
Publication statusPublished - 2014 Dec 30

Fingerprint

TATA-Box Binding Protein
binding proteins
pathogenesis
autophagy
Autophagy
Mutant Proteins
cells
Transcription
Starvation
mutants
starvation
Spinocerebellar Ataxia 17
transcription (genetics)
Chemical activation
General Transcription Factors
Peptide Initiation Factors
protein aggregates
Pathology
transfection
luciferase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Role of High Mobility Group Box 1 (HMGB1) in SCA17 pathogenesis. / Lee, Li Ching; Chen, Chiung Mei; Wang, Pin Rong; Su, Ming Tsan; Lee-Chen, Guey Jen; Chang, Chun Yen.

In: PloS one, Vol. 9, No. 12, e115809, 30.12.2014.

Research output: Contribution to journalArticle

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