AP‐1A and AP‐3A Lysosomal Sorting Functions

Heterotetrameric adaptor‐protein complexes AP‐1A and AP‐3A mediate protein sorting in post‐Golgi vesicular transport. AP‐1A and AP‐3A have been localized to the trans‐Golgi network, indicating a function in protein sorting at this compartment. AP‐3A appears to mediate trans‐Golgi network‐to‐lysosome and also endosome‐to‐lysosome protein sorting. AP‐1A is thought to be required for both trans‐Golgi network‐to‐endosome transport and endosome‐to‐trans‐Golgi network transport. However, the recent discovery of a role for monomeric GGA (Golgi localized γ‐ear containing, ARF binding protein) adaptor proteins in trans‐Golgi network to endosome protein transport has brought into question the long‐discussed trans‐Golgi network‐to‐endosome sorting function of AP‐1A. Murine cytomegalovirus gp48 contains an unusual di‐leucine‐based lysosome sorting signal motif and mediates lysosomal sorting of gp48/major histocompatibility complex class I receptor complexes, preventing exposure of major histocompatibility complex class I at the plasma membrane. We analyzed lysosomal sorting of gp48/major histocompatibility complex class I receptor complexes in cell lines deficient for AP‐1A, AP‐3A and both, to determine their sorting functions. We find that AP1‐A and AP3‐A mediate distinct and sequential steps in the lysosomal sorting. Both sorting functions are required to prevent MHC class I exposure at the plasma membrane at steady‐state.