SUPPLEMENTARY INFORMATION In format provided by Saftig and Klumperman (SEPTEMBER 2009)

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1 Lysosomal protein Synonyms Expression TM domai ns Lysosomal targeting sequence/ adaptor protein interaction Phenotype of knockout mice Discussed functions LAMP-1 LAMP-2 LGP-A; LGP120; LEP100; LAMP-A, CD107a LGP-B; LGP110; LGP96; CD107b Three isoforms: LAMP-2A LAMP-2B LAMP-2C (partially dependent on LAMP-2 isoform) 1 RKRSHAGYQTI 1 LKHHHAGYEQF (at the C-terminus; LAMP-2A) Mild regional astrogliosis, no abnormalities in other tissues; normal lysosomal morphology and function Increased postnatal mortality; accumulation of autophagic vacuoles in liver, pancreas, spleen, kidney and skeletal and heart muscle leading to cardiomyopathy and myopathy. Increased susceptibility to periodontitis. Lysosomal stability and integrity Lysosomal exocytosis Substrate for neuraminidase Lysosomal stability and integrity Chaperone-mediated autophagy (ageing, neurodegeneration) Macroautophagy Fusion of lysosomes with autophagosomes and phagosomes Lysosomal motility Overlapping function with LAMP-1 LIMP-2 LGP85; CD36L2; SCARB2 2 RGQGSTDEGTADER APLIRT Uretric pelvic junction obstruction, deafness, peripheral neuropathy, intracellular inclusions in Biogenesis and maintenance of /lysosomes Mannose 6-phosphate

2 CD63 V-type H + - ATPase Cystinosin Sialin LIMP-1; ME491; AD1 Depending on subunit PQLC4; CTNS- LSB; CTNS Solute carrier family 17 in Ubiquitous with cell-typespecific isoforms in lysosomes and but also at the plasma (renal cells, osteoclasts, macrophages, epidiymal cells) Kidney and ubiquitous other tissues Highest 4 VKSIRSGYEVM SUa: 8-9 SUc,c : 4 SUc : 5 Not determined 7 GYDQL YFPQA (at the intracellular loop between TM5 and TM6) 12 TDRTPLL (at the N-terminus) cerebral and cerebellar cortex, subtle glomerular changes, degeneration of stria vascularis Altered water balance, abnormal intracellular inclusions in principal cells of the collecting duct; lysosomal functions apparently not affected Impaired osteoclast fusion, increased bone formation (ATP6vod2); reduced insulin secretion (oc/oc; loss of subunit a3); reduced urinary acidification (ATP6v1b1); decreased osteoclast acidification (ATP6i) Cystine accumulation in many tissues; ocular changes similar to those observed in affected individuals, bone defects and behavioural anomalies; no renal pathology Not described receptor-independent transport of β- glucocerebrosidase Protein protein interaction (molecular facilitator); cell adhesion; inflammation; antigen presentation; HIV infection; regulation of ion channels Important for endocytic and intracellular traffic, processing and degradation of macromolecules, coupled transport of small molecules, entry of pathogens; bone resorption, urinary acidification, tumour cell invasion L-cystine amino acid /H + symport mechanism; presumed secondary effect on intracellular glutathione synthesis; effect on cysteinylation of protein kinase C and other cytosolic proteins Sialic acids, aspartate, glutamate transport

3 NPC-1 ClC-7 and Ostm1 CLN3 (anion/sugar transporter), member 5 OPTA2; OPTB4; CLCN7 GL; GIPN; OPTB5; HSPC019 BTS; JNCL; BATTENIN; MGC brain, heart, lung, liver Highest brain, ubiquitous expression 13 TERERLL (at the C-terminus; most likely not sufficient for lysosomal targeting) AP3-mediated targeting Lysosomal storage of nonesterified cholesterol, neurodegeneration, loss of Purkinje cells, myelin depletion, ataxia, sterility, death around 3 4 months Lysosomes - Disruption of ClC-7 and Ostm1 causes osteopetrosis (decreased bone resorption) and neurodegeneration (similar to neuronal ceroid lipofuscinosis) Brain (neuronal cells; synaptic regions) ; minor levels at the plasma 6 [M(X) 9 G]...GGEEEAESAARQP LIRTEAPE... (at the large cytosolic loop) Slightly increased mortality after 12M; mild cortical atrophy, progressive storage, motor problems and abnormal gait, retinal degeneration; no obvious cortical changes Involved in neurotransmitter release (aspartateric neurotransmission) Involved in endocytic transport, lysosomal cholesterol efflux, fatty acid efflux, regulation of lysosomal calcium levels Electrical shunt which is required for lysosomal acidification Cl-/H+ exchange mechanism Ostm1 is a monotopic accessory protein for ClC-7 and required for assembly and protein stability Discussed to be involved in arginine transport; lysosomal ph regulation; regulation of apoptosis Mucolipin MLN, ML4; MLIV; Ubiquitous 6 ETERLLTPNP Dense inclusion bodies in Putative ion channel

4 Acetyl- CoA:αglucosamide N- acetyltransfe rase MST080; TRPML1; MSTP080; TRP- ML1; TRPM-L1; MCOLN1 expression including brain, skeletal muscle, colon, thymus, liver, lung and leukocytes ; minor levels at the plasma Strong in heart, liver, kidney, placenta, leucocytes (at the N-terminus) PSEEHSLLVN 11 TALWVLIAYILYRKKI (presumed motif at the C-terminus) all cell types in brain and particularly in neurons, elevated plasma gastrin, vacuolization in parietal cells, and retinal degeneration, neurological defect. Gait deficits progress to complete hindlimb paralysis and death at age ~8 mo. Not available involved in lysosome biogenesis and defective in the lysosomal storage disorder mucolipidosis type IV Enzyme and transport function (use of cytosolic acetyl-coenzyme A for the acetylation of luminal glucosamine residues) References (1) Andrejewski, N. et al. Normal lysosomal morphology and function in LAMP-1-deficient mice. J. Biol. Chem. 274, (1999). (2) Yogalingam, G. et al. Neuraminidase 1 is a negative regulator of lysosomal exocytosis. Dev. Cell 15, (2008). (3) Tanaka, Y. et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 406, (2000). (4) Huynh, K.K. et al. LAMP proteins are required for fusion of lysosomes with phagosomes. EMBO J. 26, (2007). (5) Zhang, C. & Cuervo, A.M. Restoration of chaperone-mediated autophagy in aging liver improves cellular maintenance and hepatic function. Nat. Med. 14, (2008). (6) Eskelinen, E.L. et al. Disturbed cholesterol traffic but normal proteolytic function in LAMP-1/LAMP-2 double-deficient fibroblasts. Mol. Biol. Cell 15, (2004). (7) Gamp, A.C. et al. LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice. Hum. Mol. Genet. 12, (2003). (8) Reczek, D. et al. LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase. Cell 131, (2007). (9) Kuronita, T. et al. A role for the lysosomal protein LGP85 in the biogenesis and maintenance of endosomal and lysosomal morphology. J. Cell Sci. 115, (2002).

5 (10) Pols, M.S. & Klumperman, J. Trafficking and function of the tetraspanin CD63. Exp. Cell Res. 315, (2009). (11) Schröder, J. et al. Deficiency of the tetraspanin CD63 associated with kidney pathology but normal lysosomal function. Mol. Cell. Biol. 29, (2009). (12) Marshansky, V. & Futai, M. The V-type H + -ATPase in vesicular trafficking: targeting, regulation and function. Curr. Opin. Cell Biol. 20, (2008). (13) Forgac, M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat. Rev. Mol. Cell Biol. 8, (2007). (14) Kornak, U. et al. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nat Genet. 40, (2008). (15) Town, M. et al. A novel gene encoding an integral protein is mutated in nephropathic cystinosis. Nat Genet. 18, (1998). (16) Cherqui, S. et al. Intralysosomal cystine accumulation in mice lacking cystinosin, the protein defective in cystinosis. Mol. Cell. Biol. 22, (2002). (17) Morin, P., Sagné, C. & Gasnier, B. Functional characterization of wild-type and mutant human sialin. EMBO J. 23, (2004). (18) Kalatzis, V., Cherqui, S., Antignac, C. & Gasnier, B. Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter. EMBO J. 20, (2001). (19) Dierks, T. et al. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins. Biochim. Biophys. Acta 1793, (2009). (20) Chang, T.Y., Chang, C.C., Ohgami, N. & Yamauchi, Y. Cholesterol sensing, trafficking, and esterification. Annu. Rev. Cell Dev. Biol. 22, (2006). (21) Jentsch, T.J. CLC chloride channels and transporters: from genes to protein structure, pathology and physiology. Crit. Rev. Biochem. Mol. Biol. 43, 3 36 (2008). (22) Rakheja, D., Narayan, S.B. & Bennett, M.J. The function of CLN3P, the Batten disease protein. Mol. Genet. Metab. 93, (2008). (23) Zeevi, D.A., Frumkin, A. & Bach G. TRPML and lysosomal function. Biochim. Biophys. Acta 1772, (2007). (24) Feldhammer, M. et al. Sanfilippo syndrome type C: mutation spectrum in the heparan sulfate acetyl-coa: alpha-glucosaminide N-acetyltransferase (HGSNAT) gene. Hum. Mutat. 30, (2009)