Stress-induced Golgiphagy sustains tumor-promoting glycosylation in breast cancer

Golgiphagy contributes to Golgi quality control, yet its regulatory mechanisms and physiological functions remain poorly understood. We identify the deubiquitinase USP28 as an upstream regulator of TM9SF3-dependent Golgiphagy. Nutrient deprivation and Golgi stress induce CRM1-dependent nuclear export of USP28, enabling its translocation to the Golgi, where it removes K48-linked ubiquitin chains from TM9SF3 to prevent its proteasomal degradation and promote Golgiphagy. TM9SF3-dependent Golgiphagy regulates glycosyltransferase abundance through selective degradation of cargo such as MGAT5, thereby maintaining glycosylation homeostasis. Genetic or pharmacological inhibition of the USP28-TM9SF3-Golgiphagy pathway disrupts glycosylation homeostasis and suppresses breast tumor growth. Together, these findings establish the USP28-TM9SF3 axis as a regulatory mechanism linking Golgiphagy to glycosylation homeostasis and breast cancer progression.