Folding for the Immune Synapse: CCT Chaperonin and the Cytoskeleton

Abstract

Lymphocytes rearrange their shape, membrane receptors and organelles during cognate contacts with antigen-presenting cells (APCs). Activation of T cells by APCs through pMHC-TCR/CD3 interaction (peptide-major histocompatibility complex-T cell receptor/CD3 complexes) involves different steps that lead to the reorganization of the cytoskeleton and organelles and, eventually, activation of nuclear factors allowing transcription and ultimately, replication and cell division. Both the positioning of the lymphocyte centrosome in close proximity to the APC and the nucleation of a dense microtubule network beneath the plasma membrane from the centrosome support the T cell’s intracellular polarity. Signaling from the TCR is facilitated by this traffic, which constitutes an important pathway for regulation of T cell activation. The coordinated enrichment upon T cell stimulation of the chaperonin CCT (chaperonin-containing tailless complex polypeptide 1; also termed TRiC) and tubulins at the centrosome area support polarized tubulin polymerization and T cell activation. The proteasome is also enriched in the centrosome of activated T cells, providing a mechanism to balance local protein synthesis and degradation. CCT assists the folding of proteins coming from de novo synthesis, therefore favoring mRNA translation. The functional role of this chaperonin in regulating cytoskeletal composition and dynamics at the immune synapse is discussed.

Chaperonin CCT controls extracellular vesicle production and cell metabolism through kinesin dynamics

“…We also noticed that 495 (30%) of the proteins analysed were preferentially increased in their abundance and only 182 (11%) remained unaffected in silenced CCT cells (Figure 1b). The decrease in a large proportion of proteins produced by the drop in CCT components is consistent with the described role of CCT in the folding of newly synthesized proteins (Martín‐Cófreces et al., 2021), and in preserving the stability of proteins through protein‐protein contacts (Hodeify et al., 2018). Also, some proteins were preferentially increased (283 out of 514 detected, 55%) in siCCT cell‐derived EVs (Figure 1c).…”

“…Our data indicate a link between CCT functioning and DNA/RNA damage, opening a new perspective in the study of CCT related to maintenance of cellular homeostasis. It is known that CCT helps the folding of some checkpoint proteins for the control of cell cycle (Martín‐Cófreces et al., 2021). However, cell viability is not affected by the extent of silencing in this system, as observed previously (Martin‐Cofreces et al., 2020).…”

A genome-wide screen identifies SCAI as a modulator of the UV-induced replicative stress response in human cells

“…The RPA-ssDNA screen also identified several factors whose roles in modulating the cellular response to UV-induced replicative stress has not been as well documented compared with the above examples. TriC is a chaperone complex that assists in protein folding (Knowlton et al, 2021; Martín-Cófreces et al, 2021; Yam et al, 2008) and which has been reported to influence various cellular pathways including gene expression (Shaheen et al, 2021), cellular signalling (Weng et al, 2021), and protection against proteotoxic stress (Llamas et al, 2021). Interestingly, recent data indicate that activation of the integrated stress response, a cellular signalling cascade which responds to protein misfolding, leads to inhibition of histone gene synthesis and consequent formation of R-loops that are known to inhibit DNA RF progression (Choo et al, 2020).…”

A genome-wide screen identifies SCAI as a modulator of the UV-induced replicative stress response

“…Our screen also identified several factors whose roles in modulating the cellular response to UV-induced replicative stress has not been as well documented compared with the above examples. TRiC is a chaperone complex that assists in protein folding [ 34 , 70 , 71 ] and has been reported to influence various cellular pathways including gene expression [ 72 ], cellular signalling [ 73 ], and protection against proteotoxic stress [ 74 ]. Interestingly, recent data indicate that activation of the integrated stress response, a signalling cascade that responds to protein misfolding, leads to inhibition of histone gene synthesis and consequent formation of R-loops that are known to inhibit DNA RF progression [ 75 ].…”