A fundamental property of cellular processes is to maintain homeostasis despite varying internal and external conditions. Within the membrane transport apparatus, variations in membrane fluxes from the endoplasmic reticulum (ER) to the Golgi complex are balanced by opposite fluxes from the Golgi to the ER to maintain homeostasis between the two organelles. Here we describe a molecular device that balances transport fluxes by integrating transduction cascades with the transport machinery. Specifically, ER-to-Golgi transport activates the KDEL receptor at the Golgi, which triggers a cascade that involves Gs and adenylyl cyclase and phosphodiesterase isoforms and then PKA activation and results in the phosphorylation of transport machinery proteins. This induces retrograde traffic to the ER and balances transport fluxes between the ER and Golgi. Moreover, the KDEL receptor activates CREB1 and other transcription factors that upregulate transport-related genes. Thus, a Golgi-based control system maintains transport homeostasis through both signaling and transcriptional networks.
Highlights d ER exit sites are endowed with an auto-regulatory signaling complex called AREX d The COPII subunit Sec24 senses folded cargo and activates the AREX signaling network d AREX responds to folded cargo fluxes by regulating cargo export and protein synthesis d AREX maintains potentially harmful folded cargo in the ER at steady low levels
The sorting and distribution to different final destinations of roughly a third of the membrane and secreted proteins occurs at the level of the trans‐Golgi network (TGN). This TGN mission involves efficient mechanisms of cargo recognition and activation of specific signalling pathways. This is important because protein localization is strictly connected with function, and many aberrant phenotypes may occur when a protein is missorted to the wrong cellular compartment. In this review, we briefly summarize the principal players known to be involved in TGN functions, highlighting the importance of regulatory signalling pathways and also the pathological outcomes of aberrant sorting and export events from the TGN compartment.
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