CREB3L1-mediated functional and structural adaptation of the secretory pathway in hormone-stimulated thyroid cells

Abstract

Many secretory cells increase the synthesis and secretion of cargo proteins in response to specific stimuli. How cells couple increased cargo load with a coordinate rise in secretory capacity to ensure efficient transport is not well understood. We used thyroid cells stimulated with thyrotropin (TSH) to demonstrate a coordinate increase in the production of thyroid-specific cargo proteins and ER-Golgi transport factors, and a parallel expansion of the Golgi complex. TSH also increased expression of the CREB3L1 transcription factor, which alone caused amplified transport factor levels and Golgi enlargement. Furthermore, CREB3L1 potentiated the TSH-induced increase in Golgi volume. A dominant-negative CREB3L1 construct hampered the ability of TSH to induce Golgi expansion, implying that this transcription factor contributes to Golgi expansion. Our findings support a model in which CREB3L1 acts as a downstream effector of TSH to regulate the expression of cargo proteins, and simultaneously increases the synthesis of transport factors and the expansion of the Golgi to synchronize the rise in cargo load with the amplified capacity of the secretory pathway.

A GBF1-Dependent Mechanism for Environmentally Responsive Regulation of ER-Golgi Transport

“…The RNA-seq results also revealed upregulation of the transcription factor CREB3 (Table S1), which raises the transcription of anterograde trafficking components in response to cell activation (García et al., 2017). The degree of CREB3 upregulation inversely correlated with the level of GBF1 protein in cells (Figure 7I), as did other transcripts such as COPI and COPII components, consistent with GBF1 being part of a network that detects environmental changes and responds by controlling secretory capacity.…”

CREB3 Transcription Factors: ER-Golgi Stress Transducers as Hubs for Cellular Homeostasis

“…Transfection of active form of CREB3L1 in a pancreatic β-cell line induced expression of genes involved in protein transport and implicated extracellular matrix production (Vellanki et al, 2010). Results from our group indicate that, in thyroid cells, CREB3L1 levels are up-regulated by thyrotropin and CREB3L1 is sufficient to increase transport proteins levels and induce Golgi enlargement (Garcia et al, 2017). We also show that expression of CREB3L1 dominant negative hampers the TSH-induced Golgi enlargement.…”

Deciphering GRINA/Lifeguard1: Nuclear Location, Ca2+ Homeostasis and Vesicle Transport

“…The cAMP responsive element binding protein 3-like 1 ( CREB3L1 ) gene codes for the membrane-bound ER stress transducer OASIS, which has an important role in osteoblast differentiation during bone development [97]. OASIS promotes the expansion of the Golgi and the synthesis of transport factors to synchronize the rise in cargo load with the amplified capacity of the secretory pathway [98]. It is preferentially expressed in astrocytes in the central nervous system (CNS) [99] and modulated by the UPR to finely control astrocyte differentiation [100].…”