Golgi Stress Response: New Insights into the Pathogenesis and Therapeutic Targets of Human Diseases

Abstract

The Golgi apparatus modifies and transports secretory and membrane proteins. In some instances, the production of secretory and membrane proteins exceeds the capacity of the Golgi apparatus, including vesicle trafficking and the post-translational modification of macromolecules. These proteins are not modified or delivered appropriately due to insufficiency in the Golgi function. These conditions disturb Golgi homeostasis and induce a cellular condition known as Golgi stress, causing cells to activate the 'Golgi stress response,' which is a homeostatic process to increase the capacity of the Golgi based on cellular requirements. Since the Golgi functions are diverse, several response pathways involving TFE3, HSP47, CREB3, proteoglycan, mucin, MAPK/ ETS, and PERK regulate the capacity of each Golgi function separately. Understanding the Golgi stress response is crucial for revealing the mechanisms underlying Golgi dynamics and its effect on human health because many signaling molecules are related to diseases, ranging from viral infections to fatal neurodegenerative diseases. Therefore, it is valuable to summarize and investigate the mechanisms underlying Golgi stress response in disease pathogenesis, as they may contribute to developing novel therapeutic strategies. In this review, we investigate the perturbations and stress signaling of the Golgi, as well as the therapeutic potentials of new strategies for treating Golgi stress-associated diseases.

Regulation of virion production by the ORF8 signal peptide across SARS-CoV-2 variants

“…Like NS1, ORF8 can be secreted by conventional and unconventional secretory pathways (14,33). Golgi morphology can change when Golgi stress response is activated to cope with cells’ capacity to mature, traffic, and secrete proteins using the Golgi network (34).…”

Emerging Evidence of Golgi Stress Signaling for Neuropathies

“…When the function of the Golgi apparatus is impaired, the Golgi stress response is activated. Although the molecular mechanisms of the Golgi stress response remain largely unexplored, Figure 3 presents the six main pathways in mammals [ 20 , 27 , 28 ]. Each Golgi stress pathway is described below.…”

“…Nadanaka et al showed that the PG modified by glycosaminoglycan chains is involved in the regulation of a glycosyltransferase called EXTL2, which is involved in the synthesis of these glycans [ 32 ]. Mucin glycosylation is also part of the Golgi function and insufficient mucin glycosylation increases the transcriptional activity of mucin glycosyltransferases [ 20 , 27 , 28 ]. Mucin glycosylation occurs only in the Golgi; factors regulating the PG and mucin pathways remain unclear.…”

“…Subodio et al restored cystathionine γ–lyase (CSE), a cysteine biosynthetic enzyme, by activating the PERK/ATF4 pathway with monensin [ 61 ]. This suggests that restoring CSE function may be useful in the treatment of other diseases involving Golgi stress via the PERK/ATF4 pathway [ 28 ].…”

A NEAT Discovery Hints at Altered Golgi Signaling in Lung Fibrosis

“…Despite a more routine focus on ER stress and the UPR, Golgi stress is increasingly becoming recognized as a mechanism triggering distinct downstream signaling cascades in response to various stressors ( 21 ). For instance, the Golgi membrane protein Golgi phosphoprotein 3 (GOLPH3) has been identified as an important player in mediating morphological changes of the Golgi and downstream signaling pathways after cellular stress and injury ( 22 , 23 ).…”