Contribution of the Type II Chaperonin, TRiC/CCT, to Oncogenesis

Abstract

The folding of newly synthesized proteins and the maintenance of pre-existing proteins are essential in sustaining a living cell. A network of molecular chaperones tightly guides the folding, intracellular localization, and proteolytic turnover of proteins. Many of the key regulators of cell growth and differentiation have been identified as clients of molecular chaperones, which implies that chaperones are potential mediators of oncogenesis. In this review, we briefly provide an overview of the role of chaperones, including HSP70 and HSP90, in cancer. We further summarize and highlight the emerging the role of chaperonin TRiC (T-complex protein-1 ring complex, also known as CCT) in the development and progression of cancer mediated through its critical interactions with oncogenic clients that modulate growth deregulation, apoptosis, and genome instability in cancer cells. Elucidation of how TRiC modulates the folding and function of oncogenic clients will provide strategies for developing novel cancer therapies.

Keywords: HSP70/90; TRiC/CCT; chaperone; chaperonin; oncogenesis; oncoprotein; protein-folding; proteostasis.

Figure 1

Model of the chaperone network involving HSP70, HSP90, and TRiC (T-complex protein-1 ring complex, also known as CCT). Newly synthesized nascent polypeptide chain interacts with the HSP70 family, which mediates folding either co-translationally or post-translationally. HSP70 also can deliver a folding-intermediate to downstream chaperones HSP90 or TRiC/CCT to complete folding.

Figure 2

Molecular architecture of TRiC/CCT. (A) The end-on and side views of the X-ray crystal structure of TRiC, modified from PDB ID 2XSM, show that TRiC is a double-ringed structure composed of eight homologous but distinct subunits (CCT1–8). Each subunit is shown having a different color with the specific subunit order indicated. The black arrowhead indicates CCT1, which has unique asymmetrical features; (B) The X-ray structure of CCT1 is shown as a representative subunit. Helix-11 (H11), the putative substrate recognition site is indicated by the arrow.