The TERE1 protein interacts with mitochondrial TBL2: Regulation of trans‐membrane potential, ROS/RNS and SXR target genes

Abstract

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.

Heixuedian (heix), a potential melanotic tumor suppressor gene, exhibits specific spatial and temporal expression pattern during drosophila hematopoiesis

“…Interestingly, UBIAD1 interacts with TIRC7, a membrane protein involved in T-lymphocyte activation during the auto-immune response (McGarvey et al, 2005). Studies have shown that reduced UBIAD1 expression was found in several types of cancers such as bladder carcinoma and prostate carcinoma (Fredericks et al, 2013a;McGarvey et al, 2001McGarvey et al, , 2005. And proliferation of J82 cells (bladder cancer cell lines) was inhibited by exogenous expression of UBIAD1 (Fredericks et al, 2011), consistent with the tumor suppressor effect of Heix.…”

Structural Insights into Ubiquinone Biosynthesis in Membranes

“…Mutations in eukaryotic CoQ2 and UBIAD1 have been linked to various diseases (4–6, 26–28). Several of these mutations correspond to conserved residues (fig.…”

Bringing Bioactive Compounds into Membranes: The UbiA Superfamily of Intramembrane Aromatic Prenyltransferases

“…The majority of older SCD patients require corneal transplants due to progressive loss of visual acuity [51]. SCD-causative Ubiad1 mutations (Box 2) not only reduce the MK-4 synthesis [52], but also interfere with the binding of UBIAD1 to proteins involved in cholesterol and triglyceride metabolism [19,53]. Several proteins in this pathway, ApoE [54], TBL2 [19,53], SOAT1, and HMGCR [52], were found to interact with UBIAD1.…”

“…SCD-causative Ubiad1 mutations (Box 2) not only reduce the MK-4 synthesis [52], but also interfere with the binding of UBIAD1 to proteins involved in cholesterol and triglyceride metabolism [19,53]. Several proteins in this pathway, ApoE [54], TBL2 [19,53], SOAT1, and HMGCR [52], were found to interact with UBIAD1. In particular, SCD mutations in UBIAD1 make the UBIAD1-HMGCR complex less dissociable, which may prevent the degradation of HMGCR and result in cholesterol accumulation [55].…”

“…In Drosophila , MK4 supplementation rescues severe mitochrondial deficiency induced by Heix mutations, suggesting that this UBIAD1 homolog is essential for producing MK4 to support mitochondrial electron transport [16]. In bladder cancer cell lines, UBIAD1/TERE1 synthesizes MK4 in mitochondria but also shows non-mitochondrial localization in the ER and Golgi [53]. By contrast, UBIAD1 in corneal keratocytes localizes to mitochondria but not to the ER [59].…”