TM9SF3 is a mammalian Golgiphagy receptor that safeguards Golgi integrity and glycosylation fidelity.

Abstract

Selective autophagy of the Golgi apparatus, or Golgiphagy, depends on receptor proteins that recognize and deliver fragmented Golgi membranes into phagophores for lysosomal degradation. We recently identified TM9SF3, a Golgi-resident transmembrane protein, as a receptor mediating this process under nutrient stress and various Golgi stress conditions. TM9SF3 binds to all six mammalian Atg8 (ATG8) proteins via multiple N-terminal LC3-interacting regions (LIRs). Knockout of TM9SF3 inhibits nutrient stress-induced Golgi fragmentation, reduces autophagic delivery of Golgi components, and hinders Golgi protein degradation. In addition to nutrient stress, TM9SF3 is essential for Golgiphagy induced by monensin, brefeldin A, and glycosylation perturbations. Knockout or LIR mutation of TM9SF3 disrupts protein glycosylation, whereas its overexpression promotes the degradation of aberrantly glycosylated proteins. Notably, TM9SF3 promotes breast cancer cell proliferation, and its high expression correlates with poor patient prognosis. Our findings establish TM9SF3 as a Golgiphagy receptor essential for maintaining Golgi integrity and glycosylation fidelity, and implicate its role in supporting cancer progression.