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) (Cuervo and Dice 2000). 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) (Majeski and Dice 2004). May play a role in Parkinson disease (Gan-Or et al. 2015).

In addition, binding of the cardiac hormone, atrial natriuretic peptide (ANP), to transmembrane guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), also called LAMP1 (9.A.16.1.1) produces the intracellular second messenger cGMP in target cells. A conserved FQQI motif in the protein is essential for the internalization and subcellular trafficking of NPRA during hormone signaling in intact murine mesagial cells (Mani et al. 2016). Lamp1 mediates lipid transport, but is dispensable for autophagy in Drosophila (Chaudhry et al. 2022).

The overall transport reactions reported to be catalyzed by the lamp2a complex are:

Unfolded protein (cytoplasm) → Unfolded protein (lysosomal lumen)

Lipid (cytoplasm) → Lipid (lysosome)