9.A.16 The Lysosomal Protein Import (LPI) Family

Lysosomes take up and degrade proteins by several endocytic pathways. Additionally, they take up cytosolic proteins for degradation in a process termed chaperone-mediated autophagy. Substrate proteins contain a targeting sequence related to KFERQ. Hsc70 and cochaperones stimulate, at least in part, by unfolding the substrate prior to transport. Chaperones in the lysosomal lumen are also required for uniport. The receptor at the cytoplasmic surface is 'lysosome-associated membrane protein 2a' (lamp2a). Levels of lamp2a are regulated proportionally to the activity of the pathway. Although the translocon has not been identified, lamp2a may form the channel. It multimerizes into tetramers, octamers and higher oligomers and might insert into the membrane. The native preprotein is predicted to have 2 TMSs, one at the N-terminus and one at the C-terminus. The energy source is not known, but ATP-dependent chaperones have been implicated in the process. Other constituents are not known. LAMP1 and 2 stabilize TAPL (ABCB9; TC# 3.A.1.209.2)

The overall transport reaction catalyzed by the lamp2a complex is:

unfolded protein (cytoplasm) unfolded protein (lysosomal lumen)