Activation of ULK Kinase and Autophagy by GABARAP Trafficking from the Centrosome Is Regulated by WAC and GM130

Starvation-induced autophagy requires activation of the ULK complex at the phagophore. Two Golgi proteins, WAC and GM130, regulate autophagy, however their mechanism of regulation is unknown. In search of novel interaction partners of WAC, we found that GM130 directly interacts with WAC, and this interaction is required for autophagy. WAC is bound to the Golgi by GM130. WAC and GM130 interact with the Atg8 homolog GABARAP and regulate its subcellular localization. GABARAP is on the pericentriolar matrix, and this dynamic pool contributes to autophagosome formation. Tethering of GABARAP to the Golgi by GM130 inhibits autophagy, demonstrating an unexpected role for a golgin. WAC suppresses GM130 binding to GABARAP, regulating starvation-induced centrosomal GABARAP delivery to the phagophore. GABARAP, unlipidated and lipidated, but not LC3B, GABARAPL1, and GATE-16, specifically promotes ULK kinase activation dependent on the ULK1 LIR motif, elucidating a unique non-hierarchical role for GABARAP in starvation-induced activation of autophagy. [Display omitted] •WAC is required for ULK activation and autophagy and interacts with GM130•WAC suppresses GM130 binding to GABARAP and activates autophagy•GABARAP traffics from the pericentriolar matrix to forming autophagosomes•WAC controls the non-hierarchical activation of ULK complex by centrosomal GABARAP WAC and GM130 are two Golgi proteins that regulate autophagy. Joachim et al. show that WAC inhibits binding of the autophagy protein GABARAP to the vesicle tethering golgin GM130. This allows trafficking of the centrosomal pool of GABARAP to forming autophagosomes and GABARAP-mediated activation of the autophagy-initiating ULK1 kinase.