Role of the Lysosomal Integral Membrane Protein Type 2 (LIMP-2/SCARB2) in Lipid Transport and beyond

The lysosomal integral membrane protein type 2 (LIMP-2/SCARB2) is a multifunctional receptor and an essential component of lysosomal membranes. Previous studies focused on the elucidation of the transport of the acid hydrolase β-glucocerebrosidase (GCase) by LIMP-2 from the endoplasmic reticulum (ER) to lysosomes. The discovery of a hydrophobic cavity buried inside the large luminal domain of LIMP-2, however, indicated additional, GCase-independent, functions. The present work elucidated the function of the hydrophobic tunnel. Using a variety of cell-based assays it was demonstrated that LIMP-2 can bind the hydrophobic lipid cholesterol and cholesterol can be transported through the tunnel. Live-cell imaging studies showed that this cholesterol transport pathway plays a role in export of LDL-derived cholesterol from the lysosomal lumen across the glycocalyx lining the inside of the lysosomal limiting membrane. Loss of LIMP-2 caused lysosomal accumulation of cholesterol and a decrease in esterified cholesterol under conditions of LDL overload which resulted in aberrant signaling of the cholesterol regulatory machinery residing in the ER. In summary, the data presented in this thesis reveal that LIMP-2 can bind and transport cholesterol and while the transport is not as efficient as the well described NPC2-NPC1 route, it appears to be physiologically relevant in lysosomes and likely includes other lipids as well. In addition, LIMP-2 was shown to reside at membrane contact sites between the ER and lysosomes and co-immunoprecipitation studies indicated that it interacts with a number of contact site-mediating proteins. Finally, this study demonstrated that LIMP-2 is lipidated within its cytosolic amino- and carboxy-termini. While lack of lipidation did not interfere with correct lysosomal targeting of LIMP-2, microscopy analysis revealed enlarged lysosomes, suggesting that lipidation of LIMP-2 is vital for correct lysosome physiology.


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