The diagram is divided into two sections: Wild-type on the left and Arl8b/TBC1D9B depletion on the right. In the Wild-type section, LAMP1 exits the TGN in tubular carriers, moves to the plasma membrane, and is endocytosed. It is then sorted from the AP-3-positive compartment in an Arl8b-dependent manner. Arl8b recruits TBC1D9B, which inactivates Rab11a to prevent recycling of LAMP1 to the cell surface and facilitates fusion of LAMP1-positive vesicles with active lysosomes. In the Arl8b/TBC1D9B depletion section, increased Rab11a levels on LAMP1 vesicles lead to recycling of LAMP1 to the cell surface, delaying LAMP1 trafficking to lysosomes.
Proposed role of Arl8b and its effector, TBC1D9B, in trafficking of the newly synthesized LAMP1 to active lysosomes. Delivery of newly synthesized LAMP1 to active lysosomes follows an indirect trafficking pathway, wherein it exits the TGN in tubular carriers, followed by delivery to the plasma membrane. After endocytosis, LAMP1 is sorted from the AP-3–positive compartment in an Arl8b-dependent manner. Arl8b recruits the Rab11a GAP, TBC1D9B, which inactivates Rab11a to prevent recycling of LAMP1 to the cell surface and facilitates HOPS-mediated fusion of LAMP1-positive vesicles with pre-existing active lysosomes. Upon TBC1D9B depletion, Rab11a levels are increased on the newly synthesized LAMP1 vesicles, leading to recycling of LAMP1 to the cell surface.