IRE1-dependent GOLIM4 expression controls protein secretion to modulate glioblastoma cell adhesion and migration

One of the main glioblastoma (GB) features is the diffuse migration of the tumor cells within the surrounding brain parenchyma, rendering almost impossible the complete tumor resection and irradiation, leading to inexorable lethal relapse of the disease. In the past years, we demonstrated that IRE1α (hereafter IRE1), one of the Endoplasmic Reticulum (ER) stress sensors, plays a key role in GB biology by impacting on immune infiltration, angiogenesis and tumor cell migration/invasion, all these features being linked to an alteration of protein secretion. In the present study, we investigated if and how IRE1 could regulate the functionality of the secretory machinery in GB cells and identified GOLIM4, a Golgi-associated molecule whose expression is regulated downstream of IRE1 through the transcription of XBP1s. Interestingly, GOLIM4 silencing led to decreased surface expression of multiple molecules including MHC class I molecules, growth factor receptors (PDGFRA and IL13RA2) and proteins involved in cell-cell adhesion (CD44, CD54, NCAM1), adhesion to matrix (ITGB1) or cell migration (CD90) without alteration of their encoding transcripts’ expression levels. Moreover, GOLIM4 silencing phenotypically affected GB cell-cell adhesion and cell migration in multiple models. Overall, we have described a novel IRE1/XBP1s/GOLIM4 operon that controls the secretion of specific proteins and impacts the tumor aggressiveness.