AP-4 mediates export of ATG9A from the trans -Golgi network to promote autophagosome formation

Significance A family of adaptor protein (AP) complexes functions to sort transmembrane cargos at different stages of the endomembrane system of eukaryotic cells. AP-4 is one of the most recently described and least well-understood members of this family. Interest in this complex has risen because mutations in any of its four subunits cause a form of hereditary spastic paraplegia (HSP) with intellectual disability. In this study, we demonstrate that AP-4 sorts ATG9A, the only transmembrane component of the core autophagy machinery, from the trans -Golgi network to peripheral compartments. This sorting is required to promote the early steps of autophagosome formation. Our observations implicate AP-4 as an autophagy regulator and altered autophagy as an underlying defect in AP-4–deficient HSP.