Conflict of Interest Statement: The authors have declared that no conflicts of interest exist.
The TERE1 protein interacts with mitochondrial TBL2: Regulation of trans-membrane potential, ROS/RNS and SXR target genes
Article first published online: 18 JUL 2013
Copyright © 2013 Wiley Periodicals, Inc.
Journal of Cellular Biochemistry
Volume 114, Issue 9, pages 2170–2187, September 2013
How to Cite
Fredericks, W. J., McGarvey, T., Wang, H., Zheng, Y., Fredericks, N. J., Yin, H., Wang, L.-P., Hsiao, W., Lee, R., Weiss, J. S., Nickerson, M. L., Kruth, H. S., RauscherIII, F. J. and Malkowicz, S. B. (2013), The TERE1 protein interacts with mitochondrial TBL2: Regulation of trans-membrane potential, ROS/RNS and SXR target genes. J. Cell. Biochem., 114: 2170–2187. doi: 10.1002/jcb.24567
- Issue published online: 18 JUL 2013
- Article first published online: 18 JUL 2013
- Accepted manuscript online: 8 APR 2013 06:00AM EST
- Manuscript Accepted: 2 APR 2013
- Manuscript Received: 30 MAR 2013
- Veterans Affairs Merit Review
- The Innisfree Foundation of Bryn Mawr, PA
- The Castleman Family Fund
- LIPID METABOLISM;
- SXR TARGET GENES
We originally discovered TERE1 as a potential tumor suppressor protein based upon reduced expression in bladder and prostate cancer specimens and growth inhibition of tumor cell lines/xenografts upon ectopic expression. Analysis of TERE1 (aka UBIAD1) has shown it is a prenyltransferase enzyme in the natural bio-synthetic pathways for both vitamin K-2 and COQ10 production and exhibits multiple subcellular localizations including mitochondria, endoplasmic reticulum, and golgi. Vitamin K-2 is involved in mitochondrial electron transport, SXR nuclear hormone receptor signaling and redox cycling: together these functions may form the basis for tumor suppressor function. To gain further insight into mechanisms of growth suppression and enzymatic regulation of TERE1 we isolated TERE1 associated proteins and identified the WD40 repeat, mitochondrial protein TBL2. We examined whether disease specific mutations in TERE1 affected interactions with TBL2 and the role of each protein in altering mitochondrial function, ROS/RNS production and SXR target gene regulation. Biochemical binding assays demonstrated a direct, high affinity interaction between TERE1 and TBL2 proteins; TERE1 was localized to both mitochondrial and non-mitochondrial membranes whereas TBL2 was predominantly mitochondrial; multiple independent single amino acid substitutions in TERE1 which cause a human hereditary corneal disease reduced binding to TBL2 strongly suggesting the relevance of this interaction. Ectopic TERE1 expression elevated mitochondrial trans-membrane potential, oxidative stress, NO production, and activated SXR targets. A TERE1-TBL2 complex likely functions in oxidative/nitrosative stress, lipid metabolism, and SXR signaling pathways in its role as a tumor suppressor. J. Cell. Biochem. 114: 2170–2187, 2013. © 2013 Wiley Periodicals, Inc.