At the acidic edge: emerging functions for lysosomal membrane proteins Eeva-Liisa Eskelinen 1 , Yoshitaka Tanaka 2 and Paul Saftig 1 1 Department of Biochemistry, University of Kiel, Eduard-Buchner-Haus, Olshausenstr. 40, D-24098 Kiel, Germany 2 Kyushu University, Graduate School of Pharmaceutical Sciences, Pharmaceutical Cell Biology, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan It has recently become clear that lysosomes have more complex functions than simply being the end-point on a degradative pathway. Similarly, it is now emerging that there are interesting functions for the limiting mem- branes around these organelles and their associated proteins. Although it has been known for several dec- ades that the lysosomal membrane contains several highly N-glycosylated proteins, including the lysosome- associated membrane proteins LAMP-1 and LAMP-2 and lysosomal integral membrane protein-2/lysosomal membrane glycoprotein-85 (LIMP-2/LGP85), specific functions of these proteins have only recently begun to be recognized. Although the normal functions of LAMP-1 can be substituted by the structurally related LAMP-2, LAMP-2 itself has more specific tasks. Knock- out of LAMP-2 in mice has revealed roles for LAMP-2 in lysosomal enzyme targeting, autophagy and lysosomal biogenesis. LAMP-2 deficiency in humans leads to Danon disease, a fatal cardiomyopathy and myopathy. Furthermore, there is evidence that LAMP-2 functions in chaperone-mediated autophagy. LIMP-2/LGP85 also seems to have specific functions in maintaining endo- somal transport and lysosomal biogenesis. The pivotal function of lysosomal membrane proteins is also high- lighted by the recent identification of disease-causing mutations in cystine and sialic acid transporter proteins, leading to nephropathic cystinosis and Salla disease. Since the discovery of the lysosomal compartment by de Duve [1], much has been learned about the function of lysosomes in health and disease. Lysosomes represent the final destination for many endocytic, autophagic and secretory molecules targeted for destruction or recycling. Accordingly, numerous functions, including the turnover of cellular proteins, downregulation of surface receptors, release of endocytosed nutrients, inactivation of patho- genic organisms, repair of the plasma membrane and loading of processed antigens onto MHC class II molecules, are thought to depend on normal lysosomal function [2]. The physiological importance of lysosomes is further high- lighted by a number of diseases resulting from defects in lysosomal biogenesis and normal degradative capacity [3]. Lysosomes can be morphologically very heterogeneous owing to their numerous cellular functions and variations in content. Specifically, lysosomes are defined as hydrolase- rich, acidic organelles that lack both the cation-dependent (46 kDa) and cation-independent (300 kDa) mannose 6-phosphate receptors (MPRs). These receptors bind newly synthesized lysosomal enzymes in the trans Golgi network (TGN) and transport them to early and late endosomes where the enzymes are dissociated from the receptors as a results of the acidic pH in these organelles. MPRs can then recycle back to the TGN. The endocytic pathway also delivers substrates from the cell surface to the lysosomal compartment for degradation [4]. One crucial role of the membrane enclosing late endo- somes and lysosomes is to separate the potent luminal acid hydrolases from other cellular constituents and so protect them from unwanted degradation. The unique consti- tution of the lysosomal membrane was recognized some 20 years ago. In addition to containing cholesterol and having a characteristic phospholipid composition [5], it was reported to be extremely rich in carbohydrate [6]. Furthermore, certain lysosomal membrane proteins must mediate the essential functions of this organelle. For example, the acidification of the lysosomal lumen by a proton pump, as well as translocation of amino acids, fatty acids and carbohydrates resulting from hydrolytic degra- dation and of nutrients liberated by specific lysosomal hydrolases (vitamin B 12 and cholesterol), have all been attributed to integral proteins of the lysosomal membrane. In addition, lysosomal membrane proteins are thought to be involved in lysosomal homotypic fusion as well as in fusion with other membrane organelles, including endosomes, phagosomes and the plasma membrane [7]. In the early 1980s, two abundant glycoproteins of high molecular mass were described biochemically [8]. How- ever, a more thorough understanding of the protein com- position was achieved after the production of mono- and polyclonal antibodies directed against purified lysosomal membranes [9,10]. These studies revealed highly glycosy- lated integral proteins, in the 90–120- and 30–85-kDa ranges, that were enriched in late endosomes and/or lysosomes. These proteins were designated lysosome- associated membrane proteins (LAMPs), lysosomal membrane glycoproteins (LGPs) and lysosomal integral membrane proteins (LIMPs) (Table 1). It has been proposed that LAMPs and LIMPs are tightly packed and represent more than 50% of the total Corresponding author: Paul Saftig (psaftig@biochem.uni-kiel.de). Review TRENDS in Cell Biology Vol.13 No.3 March 2003 137 http://ticb.trends.com 0962-8924/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S0962-8924(03)00005-9