TRAP1 Chaperones the Metabolic Switch in Cancer

Abstract

Mitochondrial function is dependent on molecular chaperones, primarily due to their necessity in the formation of respiratory complexes and clearance of misfolded proteins. Heat shock proteins (Hsps) are a subset of molecular chaperones that function in all subcellular compartments, both constitutively and in response to stress. 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’. However, few effectors have been identified to date. Here, we will discuss the consequence of TRAP1 deregulation in cancer and the impact of post-translational modification on the known functions of TRAP1.

The Role of Hsp90 in Retinal Proteostasis and Disease

“…The tumour necrosis factor receptor associated protein 1 (TRAP1) is the mitochondria-specific Hsp90 isoform (HSPC5) and has distinct structural and functional properties ( Figure 1 ). Structurally, TRAP1 is similar to the cytosolic Hsp90 isoforms, with the exception of a cleavable N-terminal mitochondrial localization signal and an N-terminal extension or ‘strap’ that provides stability in its ‘closed’ conformation [ 31 ]. Functionally, TRAP1 participates in the maintenance of mitochondrial integrity, protein folding and response to proteotoxic stress in mitochondria, and protection from oxidative stress damage [ 31 , 32 ].…”

“…Structurally, TRAP1 is similar to the cytosolic Hsp90 isoforms, with the exception of a cleavable N-terminal mitochondrial localization signal and an N-terminal extension or ‘strap’ that provides stability in its ‘closed’ conformation [ 31 ]. Functionally, TRAP1 participates in the maintenance of mitochondrial integrity, protein folding and response to proteotoxic stress in mitochondria, and protection from oxidative stress damage [ 31 , 32 ]. Similarly to the ER, mitochondria are particularly vulnerable to the disturbance of proteostasis due to their high intrinsic protein folding demands.…”

Structure, Function, and Inhibitors of the Mitochondrial Chaperone TRAP1

“…Mammalian Hsp90 family proteins include Hsp90α (inducible) and Hsp90β (constitutive form) in the cytoplasm, 94 kDa glucose-regulated protein (Grp94) in the endoplasmic reticulum (ER), and tumor necrosis factor receptor-associated protein 1 (TRAP1) in the mitochondrial matrix. , All Hsp90 family proteins are overexpressed in many cancer cells to protect them from various stresses and support pro-tumorigenic pathways. − However, the function and regulation of chaperones, which are mostly dependent on their interaction with clients, cochaperones, and various modulators compartmentalized in the respective organelles, are inevitably different from one another because of their different subcellular locations . Furthermore, Hsp90α, Hsp90β, and Grp94 are essential for mouse development in consideration of sterile or embryonic lethal phenotypes upon gene knockout, − whereas TRAP1 deletion does not affect the normal development of mice .…”

“…8−10 However, the function and regulation of chaperones, which are mostly dependent on their interaction with clients, cochaperones, and various modulators compartmentalized in the respective organelles, are inevitably different from one another because of their different subcellular locations. 11 Furthermore, Hsp90α, Hsp90β, and Grp94 are essential for mouse development in consideration of sterile or embryonic lethal phenotypes upon gene knockout, 12−14 whereas TRAP1 deletion does not affect the normal development of mice. 15 This result indicates the functional difference between TRAP1 and other Hsp90 proteins.…”

An Editorial on the Special Issue ‘Hsp90 Structure, Mechanism and Disease’

“…The article by Wengert et al [ 5 ], also selected as an ‘Editor’s Choice’ article, reviewed the impact of mitochondrial TRAP1 on the regulation of mitochondrial function. TRAP1 is often upregulated in transformed cells and contributes to the ‘hallmarks of cancer’.…”