Stress in mitochondria or the endoplasmic reticulum (ER) independently causes cell death. Recently, it was reported that ER stress causes mitochondrial dysfunction via p53-upregulated modulator of apoptosis (PUMA). However, little is known regarding the mitochondria molecules that mediate ER dysfunction. The present study revealed that tumor necrosis factor receptor-associated protein 1 (TRAP1), which localizes in the mitochondria, is associated with the unfolded protein response (UPR) in the ER. TRAP1 knockdown activated the ER-resident caspase-4, which is activated by ER stress, to induce cell death in humans. However, TRAP1 knockdown cells did not show a significant increase in the level of cell death at least within 24 h after early phase of ER stress in comparison with that of the control cells. This finding could be attributed to a number of reasons. TRAP1 knockdown failed to activate caspase-9, which is activated by activated caspase-4. In addition, TRAP1 knockdown increased the basal level of GRP78/BiP expression, which protects cells, and decreased the basal level of C/EBP homologous protein (CHOP) expression, which induces cell death, even under ER stress. Thus, the present study revealed that mitochondria could be a potential regulator of the UPR in the ER through mitochondrial TRAP1.
"The decreased abundance of heat shock proteins in T2D myotubes is consistent with the hypothesis that loss of homeostatic signaling may lead to a inflammation, T2D  and aging . TNF receptor-associated protein 1 (TRAP1, also known as HSP90L or HSP75)and the redox-sensitive chaperone, PARK7, two chaperone proteins also identified in the screen, are involved in stress-induced degradation of other proteins and oxidative stress    . The observed elevation in TRAP1 protein abundance requires further validation to determine whether enhanced TRAP content may limit cell damage and regulate cell repair for restoration or apoptosis after elevated stress response . "
[Show abstract][Hide abstract] ABSTRACT: r a n s l a t i o n a l p r o t e o m i c s 2 (2 0 1 4) 25–38 ScienceDirect j o u r n a l h o m e p a g e : h t t p : / / w w w . e l s e v i e r . c o m / l o c a t e / t r p r o t In vitro Proteome Oxidative stress defense Metabolism Gene regulation Cytoskeleton Protein homeostasis maintenance Protein folding and degradation a b s t r a c t The development of insulin resistance and type 2 diabetes (T2D) involves a complex array of metabolic defects in skeletal muscle. An in vitro cell culture system excludes the acute effects of external systemic factors existing in vivo. Thus, we aimed to determine whether intrinsic differences in the protein profile exist in cultured myotubes derived from T2D versus normal glucose tolerant (NGT) healthy people. Applying two dimensional difference gel electrophoresis technology (2-D DIGE), the abundance of 47 proteins differed in myotubes derived from T2D patients versus NGT donors. Proteins involved in fatty acid and amino acid metabolism, TCA cycle, mitochondrial function, mRNA processing, DNA repair and cell survival showed higher abundance, while proteins associated with redox signaling (PARK7; Parkinson disease 7), glutathione metabolism (glutathione S-transferase, GST, isoforms T1, P1 and M2), and protein dynamics (heat shock protein, HSP, isoform B1 and 90A) showed reduced abundance in myotubes derived from T2D versus NGT donors. Consistent with our proteome analysis results, the level of total glutathione was reduced in myotubes obtained from T2D versus NGT donors. Taken together, our data provide evidence for intrinsic dif-ferences in the profile of proteins involved in energy metabolism, cellular oxidative stress, protein dynamics and gene regulation in myotubes derived from T2D patients. These dif-ferences thereby suggest a genetic or epigenetic influence on protein content level, which can be further investigated to understand the molecular underpinnings of T2D progression and lead to new therapeutic approaches.
"It has been well established that perturbation of mitochondrial function is involved in apoptosis, and many studies have reported apoptosis-related molecules around the mitochondria [17,18,48–50,63]. Apoptosis-inducing stimuli elicit the release of mitochondrial cytochrome c, which binds to Apaf-1 to activate caspase-9, one of the initiator caspases with a long pro-domain. "
[Show abstract][Hide abstract] ABSTRACT: The Golgi apparatus is important for the transport of secretory cargo. Glycosylation is a major post-translational event. Recognition of O-glycans on proteins is necessary for glycoprotein trafficking. In this study, specific inhibition of O-glycosylation (Golgi stress) induced the expression of endoplasmic reticulum (ER)-resident heat shock protein (HSP) 47 in NIH3T3 cells, although cell death was not induced by Golgi stress alone. When HSP47 expression was downregulated by siRNA, inhibition of O-glycosylation caused cell death. Three days after the induction of Golgi stress, the Golgi apparatus was disassembled, many vacuoles appeared near the Golgi apparatus and extended into the cytoplasm, the nuclei had split, and cell death assay-positive cells appeared. Six hours after the induction of Golgi stress, HSP47-knockdown cells exhibited increased cleavage of Golgi-resident caspase-2. Furthermore, activation of mitochondrial caspase-9 and ER-resident unfolded protein response (UPR)-related molecules and efflux of cytochrome c from the mitochondria to the cytoplasm was observed in HSP47-knockdown cells 24 h after the induction of Golgi stress. These findings indicate that (i) the ER-resident chaperon HSP47 protected cells from Golgi stress, and (ii) Golgi stress-induced cell death caused by the inhibition of HSP47 expression resulted from caspase-2 activation in the Golgi apparatus, extending to the ER and mitochondria.
PLoS ONE 07/2013; 8(7):e69732. DOI:10.1371/journal.pone.0069732 · 3.23 Impact Factor
"Recent findings have pointed to the putative role of TRAP1 in protecting cancer cells from the accumulation of unfolded proteins in the ER (Chae et al., 2012; Takemoto et al., 2011; Siegelin et al., 2011; Amoroso et al., 2012). Initial studies suggested that the direct inhibition of HSP90 chaperones in mitochondria is associated to an organelle unfolded protein response (UPR) triggering compensatory autophagy and secondarily ER stress (Siegelin et al., 2011). "
[Show abstract][Hide abstract] ABSTRACT: TRAP1 is a mitochondrial antiapoptotic protein up-regulated in several human malignancies. However, recent evidences suggest that TRAP1 is also localized in the endoplasmic reticulum (ER) where it is involved in ER stress protection and protein quality control of tumor cells. Based on the mechanistic link between ER stress, protection from apoptosis and drug resistance, we questioned whether these novel roles of TRAP1 are relevant for its antiapoptotic function. Here, we show for the first time that: i) TRAP1 expression is increased in about 50% of human breast carcinomas (BC), and ii) the ER stress protecting activity of TRAP1 is conserved in human tumors since TRAP1 is co-upregulated with the ER stress marker, BiP/Grp78. Notably, ER-associated TRAP1 modulates mitochondrial apoptosis by exerting a quality control on 18 kDa Sorcin, a TRAP1 mitochondrial client protein involved in TRAP1 cytoprotective pathway. Furthermore, this TRAP1 function is relevant in favoring resistance to paclitaxel, a microtubule stabilizing/ER stress inducer agent widely used in BC therapy. Indeed, the transfection of a TRAP1 deletion mutant, whose localization is restricted to the ER, in shTRAP1 cells enhances the expression of mitochondrial Sorcin and protects from apoptosis induced by ER stress agents and paclitaxel. Furthermore, BC cells adapted to paclitaxel or ER stress inducers share common resistance mechanisms: both cell models exhibit cross-resistance to single agents and the inhibition of TRAP1 by siRNAs or gamitrinib, a mitochondria-directed HSP90 family inhibitor, in paclitaxel-resistant cells rescues the sensitivity to paclitaxel. These results support the hypothesis that ER-associated TRAP1 is responsible for an extramitochondrial control of apoptosis and, therefore, an interference of ER stress adaptation through TRAP1 inhibition outside of mitochondria may be considered a further compartment-specific molecular approach to rescue drug-resistance.
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