A novel function of the monomeric CCTε subunit connects the serum response factor pathway to chaperone-mediated actin folding

• Published in: Molecular biology of the cell Vol. 26; no. 15; pp. 2801 - 2809
• Main Authors: Elliott, Kerryn L, Svanström, Andreas, Spiess, Matthias, Karlsson, Roger, Grantham, Julie
• Format: Journal Article
• Language: English
• Published: United States The American Society for Cell Biology 01.08.2015
• Subjects: Actins - metabolism; Animals; BALB 3T3 Cells; Cell Culture Techniques; Cell Line, Tumor; CELLS; Chaperonin Containing TCP-1 - genetics; Chaperonin Containing TCP-1 - metabolism; Clinical Medicine; COACTIVATOR; COMPLEX; CYTOSOLIC CHAPERONIN; DOMAIN; GELSOLIN; Humans; Klinisk medicin; Mice; Microfilament Proteins - metabolism; Molecular Chaperones - metabolism; Protein Folding; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - genetics; Serum Response Factor - metabolism; SUBSTRATE-BINDING; Trans-Activators - metabolism; TUBULIN
• ISSN: 1059-1524; 1939-4586; 1939-4586
• DOI: 10.1091/mbc.E15-01-0048

Correct protein folding is fundamental for maintaining protein homeostasis and avoiding the formation of potentially cytotoxic protein aggregates. Although some proteins appear to fold unaided, actin requires assistance from the oligomeric molecular chaperone CCT. Here we report an additional connection between CCT and actin by identifying one of the CCT subunits, CCTε, as a component of the myocardin-related cotranscription factor-A (MRTF-A)/serum response factor (SRF) pathway. The SRF pathway registers changes in G-actin levels, leading to the transcriptional up-regulation of a large number of genes after actin polymerization. These genes encode numerous actin-binding proteins as well as actin. We show that depletion of the CCTε subunit by siRNA enhances SRF signaling in cultured mammalian cells by an actin assembly-independent mechanism. Overexpression of CCTε in its monomeric form revealed that CCTε binds via its substrate-binding domain to the C-terminal region of MRTF-A and that CCTε is able to alter the nuclear accumulation of MRTF-A after stimulation by serum addition. Given that the levels of monomeric CCTε conversely reflect the levels of CCT oligomer, our results suggest that CCTε provides a connection between the actin-folding capacity of the cell and actin expression.