The Role of Tepsin in Membrane Trafficking and Autophagy
Wallace, Natalie Serina
0000-0002-9409-2721
:
2023-03-14
Abstract
Adaptor Protein 4 (AP-4) vesicles originating at the trans-Golgi network (TGN) target delivery of ATG9A, a scramblase essential for autophagosome biogenesis, to the cell periphery. AP-4 loss causes hereditary spastic paraplegia disorders, indicating AP-4 function is particularly important in neuronal cells. Tepsin is an accessory protein for AP-4 coated vesicles and a member of the epsin protein family. Genetic loss of tepsin phenocopies AP-4 loss in embryonic zebrafish, resulting in abnormal head shape and developmental delays. Tepsin ensures efficient AP-4 coat formation for ATG9A export at the TGN and affects ATG9A distribution at the cell periphery. Additionally, tepsin binds LC3B, another component of the autophagy machinery, in vitro and in cells via a LC3-interacting Region (LIR) motif. The tepsin LIR motif is important for proper ATG9A peripheral distribution. Furthermore, acute tepsin depletion in mRFP-GFP-LC3B HeLa cells increases apparent autophagosome volume and number, though autophagic flux appears unaffected. Together, these data suggest AP-4 trafficking directly affects ATG9A availability for autophagy.