Role of the Endocytic Machinery in the Sorting of Lysosome-associated Membrane Proteins

TLDR

Lysosome membranes contain lysosome‑associated membrane proteins (Lamps) that are targeted to lysosomes via tyrosine‑based sorting signals recognized by four adaptor protein complexes (AP‑1, AP‑2, AP‑3, AP‑4). The study aimed to determine the in vivo roles of these adaptor complexes and clathrin in Lamp sorting, a question that had remained unaddressed or controversial. RNA interference revealed that AP‑2 and clathrin, and to a lesser extent other AP complexes, are essential for efficient Lamp delivery to lysosomes, indicating that a substantial fraction of Lamps traffic through plasma‑membrane clathrin coats en route to lysosomes.

Abstract

The limiting membrane of the lysosome contains a group of transmembrane glycoproteins named lysosome-associated membrane proteins (Lamps). These proteins are targeted to lysosomes by virtue of tyrosine-based sorting signals in their cytosolic tails. Four adaptor protein (AP) complexes, AP-1, AP-2, AP-3, and AP-4, interact with such signals and are therefore candidates for mediating sorting of the Lamps to lysosomes. However, the role of these complexes and of the coat protein, clathrin, in sorting of the Lamps in vivo has either not been addressed or remains controversial. We have used RNA interference to show that AP-2 and clathrin-and to a lesser extent the other AP complexes-are required for efficient delivery of the Lamps to lysosomes. Because AP-2 is exclusively associated with plasma membrane clathrin coats, our observations imply that a significant population of Lamps traffic via the plasma membrane en route to lysosomes.