Figure 7. Model for TRC8 interaction with sterols and protein translation.

(A) Cells cultured in media with 10% FCS (normal lipoprotein/sterol content) undergo basal preSREBP processing (dashed arrows) and contain low levels of TRC8, which has only modest effects on growth, translation and SREBPs (indicated by the dashed lines). (B) Acute removal of sterols leads to rapid activation of preSREBPs with increases in SREBP target gene expression, including SREBPs themselves in a positive feed-forward loop (bold arrows). Production of lipid biosynthetic enzymes initiates restoration of lipid homeostasis. Initially, TRC8 does not restrain this process due to low levels, but the accumulation process begins so that by 12 to 24h of sterol deprivation (panel C), TRC8 causes a reduction of growth, reduction of translation and specific reduction of SREBPs (and other ER proteins like INSIG). This action may limit the stress of over-accumulating transmembrane proteins in an ER compartment compromised by loss of sterols and other lipids. Normalization of lipid levels occurs because TRC8-mediated reductions are not complete, permitting lipid synthesis to continue even as membrane protein accumulation becomes restricted. Moreover, reduced proliferative rates caused by accumulating TRC8 would permit restoration of lipid homeostasis by reducing requirements for membrane biogenesis. Restored lipids would then destabilize TRC8, releasing its inhibition of growth and translation.