Fine-tuning regulation of Golgi organization is mediated by proteasomal degradation

The Golgi is a dynamic organelle whose correct assembly is crucial for cellular homeostasis. Indeed, perturbations in Golgi structure are associated with numerous disorders ranging from Golgi congenital diseases to neurodegeneration and cancer. However, whether and how dispersal of the Golgi ribbon is actively regulated under stress and what are the consequences of Golgi dispersal remains unknown. By analyzing the stability of Golgi tethering factors, we found that GM130, a protein involved in ribbon formation, is degraded in response to Golgi stress in a p97/VCP and proteasome-dependent manner. While stress-induced degradation of GM130 resulted in Golgi fragmentation and cell death of Multiple Myeloma cells, ectopic expression of GM130 attenuated both phenotypes. Further, we could show in EM resolution that 26S proteasomes are associated with the cytosolic surface of Golgi membranes to facilitate Golgi Apparatus-Related Degradation (GARD). Lastly, we show that Golgi stress-induced cell death has therapeutic potential in vivo, thereby constituting a novel pathway, which may be targeted in this malignancy. Taken together, this work reveals a previously uncharacterized mechanism of Golgi-localized proteasomal degradation providing a functional link between proteostasis control and Golgi architecture, which may bear critical importance in various secretion-related human pathologies.