Last update 01 Nov 2024

TRAP1

Last update 01 Nov 2024

Basic Info

Synonyms

Heat shock protein 75 kDa, mitochondrial, HSP 75, HSP75

+ [7]

Introduction

Chaperone that expresses an ATPase activity. Involved in maintaining mitochondrial function and polarization, downstream of PINK1 and mitochondrial complex I. Is a negative regulator of mitochondrial respiration able to modulate the balance between oxidative phosphorylation and aerobic glycolysis. The impact of TRAP1 on mitochondrial respiration is probably mediated by modulation of mitochondrial SRC and inhibition of SDHA.

Drugs associated with TRAP1

ACU-D3

Target

TRAP1

Mechanism

TRAP1 antagonists

Active Org.

Accuitis, Inc.

Originator Org.

Accuitis, Inc.

Active Indication

Melanoma

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

dual HSP90/TRAP1 inhibitors (Plex Pharma)

Target

HSP90 x TRAP1

Mechanism

HSP90 inhibitors [+1]

Active Org.

Plex Pharmaceuticals, Inc.

Originator Org.

Plex Pharmaceuticals, Inc.

Active Indication

Brain metastases [+2]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

SH-491

Target

CTSK x MMP9 x TRAP1

Mechanism

CTSK inhibitors [+2]

Active Org.

East China Normal University

Originator Org.

East China Normal University

Active Indication

Osteoporosis

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TRAP1

100 Translational Medicine associated with TRAP1

0 Patents (Medical) associated with TRAP1

1,103

Literatures (Medical) associated with TRAP1

14 Oct 2024·European Heart Journal

TRAP1 drives smooth muscle cell senescence and promotes atherosclerosis via HDAC3-primed histone H4 lysine 12 lactylation

Article

Author: Chen, Shaoliang ; Xue, Mengdie ; He, Xian ; Zhang, Yunjia ; Chen, Xiang ; Li, Xuesong ; Huo, Da ; Ji, Yong ; Yin, Quanwen ; Dong, Mengdie ; Tan, Yongkang ; Wang, Xin ; Zheng, Longbin ; Jiang, Hong ; Li, Xinyu ; Chen, Hongshan ; Azam, Tayyiba ; Min, Jiao ; Chen, Minghong ; Wei, Huiyuan

AbstractBackground and AimsVascular smooth muscle cell (VSMC) senescence is crucial for the development of atherosclerosis, characterized by metabolic abnormalities. Tumour necrosis factor receptor-associated protein 1 (TRAP1), a metabolic regulator associated with ageing, might be implicated in atherosclerosis. As the role of TRAP1 in atherosclerosis remains elusive, this study aimed to examine the function of TRAP1 in VSMC senescence and atherosclerosis.MethodsTRAP1 expression was measured in the aortic tissues of patients and mice with atherosclerosis using western blot and RT–qPCR. Senescent VSMC models were established by oncogenic Ras, and cellular senescence was evaluated by measuring senescence-associated β-galactosidase expression and other senescence markers. Chromatin immunoprecipitation (ChIP) analysis was performed to explore the potential role of TRAP1 in atherosclerosis.ResultsVSMC-specific TRAP1 deficiency mitigated VSMC senescence and atherosclerosis via metabolic reprogramming. Mechanistically, TRAP1 significantly increased aerobic glycolysis, leading to elevated lactate production. Accumulated lactate promoted histone H4 lysine 12 lactylation (H4K12la) by down-regulating the unique histone lysine delactylase HDAC3. H4K12la was enriched in the senescence-associated secretory phenotype (SASP) promoter, activating SASP transcription and exacerbating VSMC senescence. In VSMC-specific Trap1 knockout ApoeKO mice (ApoeKOTrap1SMCKO), the plaque area, senescence markers, H4K12la, and SASP were reduced. Additionally, pharmacological inhibition and proteolysis-targeting chimera (PROTAC)-mediated TRAP1 degradation effectively attenuated atherosclerosis in vivo.ConclusionsThis study reveals a novel mechanism by which mitonuclear communication orchestrates gene expression in VSMC senescence and atherosclerosis. TRAP1-mediated metabolic reprogramming increases lactate-dependent H4K12la via HDAC3, promoting SASP expression and offering a new therapeutic direction for VSMC senescence and atherosclerosis.

01 Oct 2024·Journal of Molecular Medicine

TRAP1 modulates mitochondrial biogenesis via PGC-1α/TFAM signalling pathway in colorectal cancer cells

Article

Author: Garofoli, Marianna ; Bruno, Giuseppina ; Piscazzi, Annamaria ; Giordano, Guido ; Pietrafesa, Michele ; Conteduca, Vincenza ; Esposito, Franca ; Porras, Almudena ; Landriscina, Matteo ; Crispo, Fabiana ; Maddalena, Francesca

AbstractMetabolic rewiring promotes cancer cell adaptation to a hostile microenvironment, representing a hallmark of cancer. This process involves mitochondrial function and is mechanistically linked to the balance between mitochondrial biogenesis (MB) and mitophagy. The molecular chaperone TRAP1 is overexpressed in 60–70% of human colorectal cancers (CRC) and its over-expression correlates with poor clinical outcome, being associated with many cancer cell functions (i.e. adaptation to stress, protection from apoptosis and drug resistance, protein synthesis quality control, metabolic rewiring from glycolysis to mitochondrial respiration and vice versa). Here, the potential new role of TRAP1 in regulating mitochondrial dynamics was investigated in CRC cell lines and human CRCs. Our results revealed an inverse correlation between TRAP1 and mitochondrial-encoded respiratory chain proteins both at transcriptional and translational levels. Furthermore, TRAP1 silencing is associated with increased mitochondrial mass and mitochondrial DNA copy number (mtDNA-CN) as well as enhanced MB through PGC-1α/TFAM signalling pathway, promoting the formation of new functioning mitochondria and, likely, underlying the metabolic shift towards oxidative phosphorylation. These results suggest an involvement of TRAP1 in regulating MB process in human CRC cells.Key messages

TRAP1 inversely correlates with protein-coding mitochondrial gene expression in CRC cells and tumours.

TRAP1 silencing correlates with increased mitochondrial mass and mtDNA copy number in CRC cells.

TRAP1 silencing favours mitochondrial biogenesis in CRC cells.

08 Aug 2024·Nature

In vivo single-cell CRISPR uncovers distinct TNF programmes in tumour evolution

Article

Author: Khandekar, Ameya ; Kretz, Jonas A ; Ellis, Stephanie J ; Duré, Clara ; Lee, Minkyoung ; Baghai Sain, Simona ; Bernasconi, Martino ; Valdivia-Francia, Fabiola ; Hyams, Katie ; Pohly, Marcel ; Ghoshdastider, Umesh ; Ficht, Xenia ; Forny, Merima ; Renz, Peter F ; Ormiston, Mark ; Moor, Andreas E ; Sendoel, Ataman

AbstractThe tumour evolution model posits that malignant transformation is preceded by randomly distributed driver mutations in cancer genes, which cause clonal expansions in phenotypically normal tissues. Although clonal expansions can remodel entire tissues1–3, the mechanisms that result in only a small number of clones transforming into malignant tumours remain unknown. Here we develop an in vivo single-cell CRISPR strategy to systematically investigate tissue-wide clonal dynamics of the 150 most frequently mutated squamous cell carcinoma genes. We couple ultrasound-guided in utero lentiviral microinjections, single-cell RNA sequencing and guide capture to longitudinally monitor clonal expansions and document their underlying gene programmes at single-cell transcriptomic resolution. We uncover a tumour necrosis factor (TNF) signalling module, which is dependent on TNF receptor 1 and involving macrophages, that acts as a generalizable driver of clonal expansions in epithelial tissues. Conversely, during tumorigenesis, the TNF signalling module is downregulated. Instead, we identify a subpopulation of invasive cancer cells that switch to an autocrine TNF gene programme associated with epithelial–mesenchymal transition. Finally, we provide in vivo evidence that the autocrine TNF gene programme is sufficient to mediate invasive properties and show that the TNF signature correlates with shorter overall survival of patients with squamous cell carcinoma. Collectively, our study demonstrates the power of applying in vivo single-cell CRISPR screening to mammalian tissues, unveils distinct TNF programmes in tumour evolution and highlights the importance of understanding the relationship between clonal expansions in epithelia and tumorigenesis.

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TRAP1

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