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Woodford, M.; , .; Bourboulia, D.; Mollapour, M. Impact of TRAP1 on Cancer Metabolism. Encyclopedia. Available online: https://encyclopedia.pub/entry/23792 (accessed on 12 December 2024).
Woodford M,  , Bourboulia D, Mollapour M. Impact of TRAP1 on Cancer Metabolism. Encyclopedia. Available at: https://encyclopedia.pub/entry/23792. Accessed December 12, 2024.
Woodford, Mark, , Dimitra Bourboulia, Mehdi Mollapour. "Impact of TRAP1 on Cancer Metabolism" Encyclopedia, https://encyclopedia.pub/entry/23792 (accessed December 12, 2024).
Woodford, M., , ., Bourboulia, D., & Mollapour, M. (2022, June 07). Impact of TRAP1 on Cancer Metabolism. In Encyclopedia. https://encyclopedia.pub/entry/23792
Woodford, Mark, et al. "Impact of TRAP1 on Cancer Metabolism." Encyclopedia. Web. 07 June, 2022.
Impact of TRAP1 on Cancer Metabolism
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This entry is adapted from the peer-reviewed paper 10.3390/biom12060786

The Hsp90 chaperone TNF-receptor-associated protein-1 (TRAP1) is primarily localized to the mitochondria and controls both cellular metabolic reprogramming and mitochondrial apoptosis. TRAP1 upregulation facilitates the growth and progression of many cancers by promoting glycolytic metabolism and antagonizing the mitochondrial permeability transition that precedes multiple cell death pathways. TRAP1 attenuation induces apoptosis in cellular models of cancer, identifying TRAP1 as a potential therapeutic target in cancer. Similar to cytosolic Hsp90 proteins, TRAP1 is also subject to post-translational modifications (PTM) that regulate its function and mediate its impact on downstream effectors, or ‘clients’.

TRAP1 Hsp90 chaperone post-translational modification cancer mitochondria metabolism Warburg effect

1. Introduction

Molecular chaperones of the heat shock protein-90 (Hsp90) family are involved in signal integration and the cellular stress response. These chaperones mediate cell signaling through the stabilization and activation of their substrate proteins, known as clients (https://www.picard.ch/downloads/Hsp90interactors.pdf, accessed 28 February 2022) [1]. The Hsp90 chaperone function is coupled to the ability to hydrolyze ATP, and chaperone activity can be precisely regulated by a heterogeneous group of proteins known as co-chaperones [2], as well as a diverse array of post-translational modifications (PTM) [3].
TNF-receptor-associated protein-1 (TRAP1) is the mitochondrial-dedicated Hsp90 family member and is localized to the mitochondrial matrix, inner mitochondrial membrane, and the intermembrane space [4][5][6]. TRAP1 was first identified through its interaction with the intracellular domain of the Type I TNF receptor [7], and early characterization of TRAP1 demonstrated ATP-binding ability and sensitivity to ATP-competitive Hsp90 inhibitors [8]. Despite this, TRAP1 was unable to form complexes with known cytosolic Hsp90 co-chaperones, nor could it promote the maturation of Hsp90 client proteins, suggesting a distinct mechanism of action for TRAP1 [8].
From this time, work has concentrated on the impact of TRAP1 on cellular processes, however identification of TRAP1 effectors and regulatory mechanisms of TRAP1 expression and activity are critical to understanding its biological function. TRAP1 has an established role as a master regulator of metabolic flux, and a large body of evidence has demonstrated that TRAP1 expression serves to suppress oxidative phosphorylation [9][10][11]. Further, TRAP1 also contributes to cell survival through complex formation with cyclophilin D (CypD), which regulates the opening of the permeability transition pore (PTP) [12]. These two known roles suggest a critical function for TRAP1 in maintaining cellular homeostasis [13].

2. Structural Basis of TRAP1 Activity

Hsp90 family chaperones are characterized by their dimeric structure. Each of the two protomers are composed of an amino-terminal ATP-binding domain, followed by a middle domain, the primary interface for client interaction, and a C-terminal domain that allows constitutive dimerization of the protomers [14]. Hsp90 chaperone activity is coupled to its ability to hydrolyze ATP [15][16]. The ‘chaperone cycle’ begins with ATP binding to the ‘open’ conformation of Hsp90, followed by transient dimerization of the N-terminal domains of each protomer and ATP hydrolysis, and subsequent release of mature client proteins and regeneration of the ‘open’ Hsp90 dimer [17]. TRAP1 is broadly structurally similar to cytosolic Hsp90, with some notable exceptions, including a cleavable N-terminal mitochondrial localization signal and an N-terminal extension or ‘strap’ that stabilizes the ‘closed’ conformation of TRAP1 [18][19]. Asymmetrical post-translational modification and co-chaperone binding are important determinants of Hsp90 molecular chaperone function [18][20][21][22][23][24]. Interestingly, TRAP1 dimers are inherently asymmetric, and uniquely composed of one ‘straight’ and one ‘buckled’ protomer, with the buckled protomer demonstrating increased rates of ATP hydrolysis [25] (Figure 1). Recently, structural and cell-based studies have described a tetrameric form of TRAP1 induced in response to dysregulation of oxidative metabolism, although the impact of this TRAP1 state on its activity is as yet unknown [26]. Interestingly, whether TRAP1 ATPase activity is essential for the entire scope of its biological role also remains an open question [26].
Figure 1. Structures of human TRAP1 (PDB: 6xg6) and human Hsp90β (PDB: 5fwp) bound to nucleotide with the conserved N-, middle-, and C-domains denoted. One protomer of each is colored blue and the second is colored green. The regulatory N-terminal extension (strap) of each TRAP1 protomer can be observed overlapping the opposite protomer. The region of TRAP1 near the M-C boundary that ‘buckles’ during conformational rearrangement is incompletely resolved in the structure. Additionally, the resolved residues of the charged linker domain (CL) of cytosolic Hsp90, which is absent in TRAP1, are labeled in the lower right quadrant.

3. Impact of TRAP1 on Cancer Metabolism

Controversially, TRAP1 has alternately been characterized as an oncogene and tumor suppressor, and it has been suggested that TRAP1 is essential for malignant transformation of cells but dispensable at later stages of tumor development [6][27]. Despite this controversy, much of the literature supports the idea that TRAP1 regulates metabolic transformation during tumorigenesis, TRAP1 is overexpressed in many cancers, and TRAP1 attenuation is detrimental to tumor cell survival [28][29][30][31][32][33]. It may be more appropriate to suggest that, similar to cytosolic Hsp90, many cancers may be ‘addicted’ to TRAP1 [34][35][36]. In fact, multiple pathways in which TRAP1 activity can drive tumorigenesis have been described (Figure 2).
Figure 2. Role of human TRAP1 in mitochondria of normal cells and cancer cells. Normal expression levels (light blue) lead to TRAP1 regulation of ROS and calcium levels, integrity of cristae, function of ETC, and oversight of the PTP. As TRAP1 expression increases (dark blue), mitochondria lose calcium sensitivity, downregulate ROS, and prevent PTP opening, leading to metabolic reprogramming and evasion of apoptosis in cancer.

3.1. Metabolic Regulation

The cellular energy currency adenosine triphosphate (ATP) is generated as a consequence of the complete oxidation of glucose to CO2 and H2O, and each molecule of glucose can maximally result in 36–38 ATP molecules [37]. Normal cells produce ATP primarily through cellular respiration, which describes a process in which glucose metabolism by glycolysis is coupled to the tricarboxylic acid cycle (TCA). Concurrent mitochondrial electron transport generates the electrochemical gradient that provides the force by which ATP is disseminated throughout the cell [38]. ATP generation is highly dysregulated in cancers, and many cancer subtypes supplement their ATP supply by upregulating cytosolic glycolysis, simultaneously generating additional ATP driven by the terminal fermentation of pyruvate to lactate [39]. This hyperactive glycolytic phenotype is known as the Warburg effect, and serves to support the accelerated growth of cancers through the increased synthesis of intermediates for anaplerotic metabolism and hypertrophy [40][41]. The phenotypic manifestations of metabolic dysregulation are variable and dependent on cell type and genotype, and many of the details and nuances of this differential regulation remain obscured.
Few specific biological roles and binding partners have been described for TRAP1, despite the broad understanding of its impact on metabolic flux. Two of the few described bona fide clients of TRAP1 however are subunits of electron transport chain (ETC) complexes, Complex II components succinate dehydrogenase subunit A/B (SDHA/B) [42][43][44][45], and Complex IV cytochrome c oxidase subunit 2 (COXII) [6][46][47]. Complex II/SDH is an iron–sulfur cluster-containing protein complex that functions to transfer electrons from succinate to coenzyme Q10-ubiquinone (Complex III) [48]. In agreement with the understanding of Hsp90 function, TRAP1 maintains SDH in a partially unfolded state [49], and TRAP1 inhibition releases active SDH, leading to an increase in its activity [27][44][50][51][52]. Further, SDH activity [44][53][54] and the oxygen consumption rate [6][55] are inversely correlated with TRAP1 expression, implicating TRAP1 in promoting the Warburg effect [56]. Notably, SDH also oxidizes succinate to fumarate and thus integrates the TCA cycle and the ETC, indicative of the broad influence of TRAP1 on mitochondrial metabolism [56][57][58].
Complex IV of the ETC converts molecular oxygen to water, and in doing so enacts the final step in generating the electrochemical gradient that supports ATP production by Complex V (ATP synthase) [59]. COXII is a downstream effector of TRAP1 function in the regulation of apoptosis, and TRAP1 regulates COXII expression [47] and activity [6]. As downregulation or inhibition of TRAP1 has been shown to destabilize COXII [46][50] and deletion of TRAP1 was associated with decreased COXIV subunit levels [60], it is possible that TRAP1 chaperoning of COXII/IV is mechanistically similar to SDHA/B. TRAP1 has also been shown to interact with the Complex V subunit ATPB, although little is known about this interaction [27].
Mitochondrial respiration drives the production of reactive oxygen species (ROS) and is responsible for most cellular ROS (Figure 3) [61]. In considering the role of TRAP1 in chaperoning SDH and COXII, TRAP1-mediated regulation of mitochondrial respiration suppresses ROS production [62], thereby contributing to the regulation of redox homeostasis, metabolic flux, and mitochondrial apoptosis.
Figure 3. Simplified mitochondrial respiration schematic. Electron transport chain (ETC) complexes (I–V) are represented by orange ovals, and reactive oxygen species (ROS) generated as a byproduct of Complex I and III activity is represented by yellow starbursts. Succinate dehydrogenase (SDH)/Complex II connects the ETC to the tricarboxylic acid (TCA) cycle. TRAP1 interactors involved in this process have been highlighted in green.

3.2. Contribution to Tumorigenesis

Cancer-associated increases in TRAP1 expression suggest a role for TRAP1 in oncogenesis [30][63][64]. Indeed, TRAP1 deletion delayed tumor formation in a mouse model of breast cancer, providing direct evidence of the role of TRAP1 in tumor initiation [65]. Further, TRAP1-mediated SDH inhibition leads to accumulation of the oncometabolite succinate [58]. Increased succinate inhibits the activity of prolyl hydroxylases, which are responsible for the hydroxylation of the transcription factor hypoxia inducible factor (HIF1α), a prerequisite for recognition by the VHL-dependent E3-ubiquitin ligase machinery [66]. Succinate-dependent HIF1α stabilization and activation promotes a well-established glycolytic transcriptional program [67], demonstrating yet another function of TRAP1 in the regulation of cancer-associated metabolic dysregulation.
TRAP1 expression was found to be elevated in aggressive pre-neoplastic lesions in a rat model of hepatocarcinogenesis [68]. The master antioxidant transcription factor NRF2 was also activated in this model, and given the established role of TRAP1 in regulating intracellular ROS, TRAP1 likely participates in NRF2-driven ROS mitigation during tumor development [68]. NRF2 inhibition led to decreased TRAP1 levels independent of TRAP1 transcription [68], suggesting that post-translational regulation is essential for sustained TRAP1 expression in pre-cancerous and cancerous cells. Interestingly, pentose phosphate pathway (PPP) flux was found to be increased in this model, and was determined to be a consequence of elevated citrate synthase activity in aggressive pre-neoplastic lesions [68]. Citrate accumulation inhibits downstream metabolic enzymes phosphofructokinase and SDH and activates the anaplerotic PPP [69]. This increase in citrate synthase activity was alleviated following TRAP1 knockdown or inhibition, suggesting that citrate synthase may also be a TRAP1 client [68].
Cell cycle dysregulation is a well-established driver of tumorigenesis [70]. TRAP1 impacts the cell cycle through regulation of protein quality control in cooperation with the proteasome regulator TBP7 [71][72]. Loss of the TRAP1/TBP7 machinery leads to increased ubiquitination and degradation of the G2-M checkpoint proteins CDK1 and MAD2 and dysregulation of mitotic entry [72]. However, whether TBP7 is a client or perhaps even the first co-chaperone of TRAP1 remains to be seen.
Taken together, these data describe multiple mechanisms through which TRAP1 dysregulation can impact cellular metabolic flux and, potentially, tumorigenesis.

3.3. Evasion of Apoptosis

Mitochondrial involvement in cell death is mediated by the release of cytochrome c [73][74]. Sustained opening of the permeability transition pore (PTP) within the inner mitochondrial membrane (IMM) initiates a series of events that lead to cytochrome c release and apoptosis or necrosis. Upon PTP opening, particles under 1500 Da, such as ions (Ca2+, K+, and H+), water, and other solutes, flood the IMM, causing swelling and unfolding of the cristae and eventual outer mitochondrial membrane (OMM) rupture. Subsequent efflux of cytochrome c through the compromised OMM into the cytosol induces the caspase cascade [75][76]. This sustained PTP opening is known as the mitochondrial permeability transition (PT) [77], and it can be triggered by several mechanisms, including elevated ROS, Ca2+, or inorganic phosphate levels, as well as decreased pH or ATP depletion [78]. Interplay between these elements also plays a role in its regulation, as elevated ROS has been shown to decrease the amount of Ca2+ required to trigger the PTP [76].
TRAP1 attenuation induces opening of the PTP and release of cytochrome c [47], and expression of TRAP1 likely discourages the initiation of apoptosis through two distinct, but potentially overlapping mechanisms: (1) regulation of triggers that signal into the PTP, and (2) direct disruption of the physical mechanism of PTP opening. TRAP1 knockdown has been shown to lead to increased ROS accumulation under oxidative stress [79] and TRAP1 overexpression insulates cells against iron chelation-mediated ROS production [80]. These effects are likely a consequence of both direct and indirect roles of TRAP1 in minimizing ROS generation. TRAP1 is a direct regulator of oxidative phosphorylation through its chaperoning of Complexes II and IV of the ETC [6][44][46] and has an indirect role in quenching existing ROS, as TRAP1 expression is associated with increased levels of the reduced form of the antioxidant glutathione (GSH) [81]. TRAP1-dependent regulation of ROS generation also results in decreased oxidation of the phospholipid cardiolipin. This phospholipid is responsible for the binding of cytochrome c to the inner folds of cristae, and its oxidation results in an increase of free cytochrome c in the inner membrane space that can potentially escape into the cytosol [78].
Furthermore, TRAP1 has been shown to chaperone the calcium-binding protein Sorcin [82]. TRAP1 is also thought to be responsible for Sorcin translocation into the mitochondria, given that Sorcin lacks its own mitochondrial localization sequence [8][82]. Overexpression of Sorcin in neonatal cardiac myocytes has been shown to increase mitochondrial Ca2+ levels, while simultaneously decreasing cytochrome c release, indicating an increase in mitochondrial Ca2+ tolerance [83]. Therefore, the chaperoning of Sorcin by TRAP1 is important for desensitizing the PTP to Ca2+ levels. Understanding this regulation is particularly important for TRAP1, as Ca2+ can replace Mg2+ as a co-factor and induce an increased rate of TRAP1 ATP hydrolysis [84]. TRAP1 has also been shown to decrease ubiquitination of the mitochondrial contact site and cristae organizing system subunit 60 (MIC60) under conditions of extracellular acidosis [85]. MIC60 is a critical component of the protein complex MICOS, which is regarded as the master organizer of the IMM through the formation of contact sites with the outer membrane and maintenance of cristae junctions [86][87]. Thus, TRAP1 regulation of MIC60 contributes to its anti-apoptotic function through the preservation of mitochondrial integrity.
Proposals for the structure of the PTP have gone through various iterations, however the prevailing model is that the PTP is formed by coordinated activities of the adenine nucleotide translocator (ANT) and the F-ATP synthase [88][89][90]. Furthermore, cyclophilin D (CypD) is key to PTP regulation [12][91]. Though its role in this process is controversial, CypD peptidyl-prolyl isomerase activity is required, as is its binding to the mitochondrial peripheral stalk subunit of the F-ATP synthase [63][90][92]. In addition to attenuating the triggers that lead to PTP opening, TRAP1 has been shown to antagonize the opening of the PTP itself. There is a general consensus that TRAP1 accomplishes this by forming a complex with CypD, interfering with the ability of CypD to interact with the PTP [12][63][93] potentially at the peripheral stalk of F-ATP synthase [90].
Further, the mitochondrial chaperones Hsp60 and Hsp90 have been implicated in this process, as their association with CypD also prevents PTP opening; however, the architecture of this complex has yet to be characterized [12][63][93][94][95][96].

4. Post-Translational Regulation of TRAP1

Post-translational modification is critically important to mitochondrial function [97] and has previously been shown to regulate TRAP1, though relatively little is known about individual PTM sites (Table 1, Figure 4) [5][6][98][99]. A comprehensive study of cytosolic Hsp90 has demonstrated the importance of post-translational regulation to Hsp90 chaperone activity (reviewed in [3][100]), and in the absence of certain co-chaperone regulatory proteins, specific PTM events have been shown to functionally recapitulate their activity [101]. This phenomenon may be critically important for TRAP1 biology, as TRAP1 is thought to act without the assistance of co-chaperones [8][10].
Figure 4. Ribbon structure of human TRAP1 (PDB: 6xg6) with known PTM sites. C501 (yellow) and S511 (red) are highlighted, while S568 is absent.
Table 1. Reported PTMs of TRAP1. Paralog identifies conserved residues in Hsp90α. GSNOR—S-nitrosoglutathione reductase, ERK—extracellular signal-regulated kinase.

Modification

Enzyme

Residue

Paralog

Impact on TRAP1

Reference

S-Nitrosylation

GSNOR

Cys501

Thr495

Decreased activity,

proteasomal degradation

[98]

Phosphorylation

ERK1/2

Ser511

Ser505

N/A

[10]

Phosphorylation

ERK1/2

Ser568

Glu562

Increased SDH inhibition

[10]

S/T Phosphorylation

PINK1

N/A

N/A

N/A

[5]

Y Phosphorylation

Unknown,

possibly c-Src

N/A

N/A

Disrupts c-Src interaction

[6]

Deacetylation

SIRT3

N/A

N/A

Increased activity

[27]

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Mark Woodford
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