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Acid Phosphatase 5 Is Responsible for Removing the Mannose 6-Phosphate Recognition Marker from Lysosomal Proteins

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Acid Phosphatase 5 Is Responsible for Removing the Mannose 6-Phosphate Recognition Marker from Lysosomal Proteins Acid phosphatase 5 is responsible for removing the mannose 6-phosphate recognition marker from lysosomal proteins Pengling Suna, David E. Sleata, Miche` le Lecocqb, Alison R. Haymanc, Michel Jadotb, and Peter Lobela,1 aCenter for Advanced Biotechnology and Medicine and Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854; bLaboratoire de Chimie Physiologique, Unite´de Recherche en Physiologie Mole´culaire, Faculte´s Universitaires Notre-Dame de la Paix, 61 rue de Bruxelles, 5000-Namur, Belgium; and cSchool of Clinical Veterinary Science, University of Bristol, Bristol BS40 5DU, UK Edited by Stuart A. Kornfeld, Washington University School of Medicine, St. Louis, MO, and approved September 12, 2008 (received for review July 31, 2008) Most newly synthesized proteins destined for the lysosome reach Golgi to repeat the process or to the plasma membrane. At the this location via a specific intracellular pathway. In the Golgi, a latter location, the CI-MPR can function in the endocytosis and phosphotransferase specifically labels lysosomal proteins with lysosomal targeting of extracellular Man-6-P glycoproteins. mannose 6-phosphate (Man-6-P). This modification is recognized Early studies indicated that Man-6 phosphorylation was a by receptors that target the lysosomal proteins to the lysosome transient modification of lysosomal proteins that was removed where, in most cell types, the Man-6-P recognition marker is rapidly with a half-life of 1.4 h in mouse lymphoma cells (3) and also removed. Despite extensive characterization of this pathway, the rapidly removed in CHO cells (4). The exact site of dephos- enzyme responsible for the removal of the targeting modification phorylation is not clear, and there is evidence suggesting that it has remained elusive. In this study, we have identified this activity. may occur in both a prelysosomal compartment (5) and a dense Preliminary investigations using a cell-based bioassay were used to postendosomal compartment that probably represents the lyso- follow a dephosphorylation activity that was associated with the some itself (6). The rate and the extent of removal of the lysosomal fraction. This activity was high in the liver, where Man-6-P recognition marker in cell culture are dependent on endogenous lysosomal proteins are efficiently dephosphorylated, cell-type and culture conditions. For example, the Man-6-P but present at a much lower level in the brain, where the modi- modification was found to persist in cells lacking the CI-MPR fication persists. This observation, combined with an analysis of (4). In addition, mouse L cells remove the Man-6-P modification the expression of lysosomal proteins in different tissues, led us to normally when grown at low density but accumulate Man-6-P identify acid phosphatase 5 (ACP5) as a candidate for the enzyme glycoproteins when grown at high density or in the absence of that removes Man-6-P. Expression of ACP5 in N1E-115 neuroblas- serum (7, 8). Man-6-P glycoproteins endocytosed by the L-cells toma cells, which do not efficiently dephosphorylate lysosomal in the absence of serum were restricted to a subset of lysosomes, proteins, significantly decreased the steady state levels of Man6-P suggesting that there may be lysosomal populations with distinct glycoproteins. Analysis of ACP5-deficient mice revealed that levels functions that differ in their ability to remove the Man-6-P of Man-6-P glycoproteins were highly elevated in tissues that modification (8). normally express ACP5, and this resulted from a failure to dephos- Cell-specific differences in the removal of the Man-6-P rec- phorylate lysosomal proteins. These results indicate a central role ognition marker have also been observed under physiological for ACP5 in removal of the Man-6-P recognition marker and open conditions. Although rat liver has higher levels of most lysosomal up new avenues to investigate the importance of this process in cell enzyme activities than rat brain, the actual proportion of these biology and medicine. activities that are represented by the Man-6-P-containing form of each enzyme is dramatically less in the liver than in the brain dephosphorylation ͉ lysosome ͉ protein targeting (9). In the brain, Man-6-P-containing glycoproteins predomi- nantly accumulate within the lysosomes that are present in neuronal cell bodies (10). he lysosome is an acidic membrane-delimited organelle that The cellular activity that is responsible for the removal of the plays a critical role in the cellular digestion of a diverse range T Man-6-P recognition marker has not been identified. It could of macromolecules including proteins, carbohydrates, nucleic conceivably be a glycosidase or isomerase but is most likely a acids, and lipids (1). These catabolic functions are conducted phosphatases, and several studies have investigated the role of primarily by the concerted actions of over 60 soluble luminal two lysosomal hydrolases, acid phosphatase 2 (ACP2, also called hydrolases and accessory proteins, most of which are targeted to lysosomal acid phosphatase) and acid phosphatase 5 (ACP5, also the lysosome by a common pathway (reviewed in ref. 2). Central called tartrate-resistant acid phosphatase or uteroferrin) in the to this pathway is a posttranslational modification that is largely removal of Man-6-P from lysosomal proteins. ACP2 is trans- specific to lysosomal proteins, mannose 6-phosphate (Man-6-P). ported to the lysosome in a membrane-bound form and then is Like other glycoproteins, soluble lysosomal proteins are synthe- proteolytically cleaved to release a soluble phosphatase (11), sized in the endoplasmic reticulum and are cotranslationally whereas ACP5 is a soluble lysosomal protein that is targeted via glycosylated on select asparagine residues. As these proteins the Man-6-P pathway (12). Both enzymes hydrolyze a variety of move through the secretory pathway, the lysosomal proteins are selectively recognized by a phosphotransferase that initiates a two-step reaction that results in the generation of the Man-6-P Author contributions: P.S., D.E.S., M.L., M.J., and P.L. designed research; P.S., M.L., and modification on specific N-linked oligosaccharides. The modi- A.R.H. performed research; A.R.H. contributed new reagents/analytic tools; P.S., D.E.S., fied proteins are then recognized by two Man-6-P receptors M.L., M.J., and P.L. analyzed data; and P.S., D.E.S., and P.L. wrote the paper. (MPRs), the cation-dependent MPR and the cation-indepen- The authors declare no conflict of interest. dent (CI-) MPR. These receptors bind the phosphorylated This article is a PNAS Direct Submission. lysosomal proteins in the near neutral pH environment of the 1To whom correspondence should be addressed. E-mail: [email protected]. transGolgi network and travel to an acidic prelysosomal com- This article contains supporting information online at www.pnas.org/cgi/content/full/ partment in which the low pH promotes dissociation of the 0807472105/DCSupplemental. receptors and ligands. The receptors then recycle back to the © 2008 by The National Academy of Sciences of the USA 16590–16595 ͉ PNAS ͉ October 28, 2008 ͉ vol. 105 ͉ no. 43 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0807472105 Downloaded by guest on September 25, 2021 phosphomonoesters at acid pH in vitro, but their physiological brain. The liver extract allows the N1E-115 cells to dephosphor- substrates are unknown. ACP2 was overexpressed by a factor of ylate Ϸ80% of the Man-6-P containing forms of lysosomal 100-fold in mouse L cells, but this failed to increase the slow rate proteins, whereas dephosphorylation in cells cultured with the of removal of Man-6-P and purified ACP2 did not dephosphor- brain extract was considerably less (Ϸ20%) (data not shown). ylate arylsulfatase A in vitro (13). These data suggest that ACP2 This finding is congruent with our measurements of steady-state is not involved in the removal of Man-6-P under physiological phosphorylation in vivo, indicating physiological relevance. conditions. In contrast, ACP5 can efficiently dephosphorylate Second, the dephosphorylation activity is associated with arylsulfatase A in vitro and was originally considered a likely lysosomes. We conducted classical analytical subcellular frac- candidate for the Man-6-phosphatase (6). However, subsequent tionation to determine what membrane-delimited cellular com- studies on fibroblasts from mice that were deficient in both partment contains the dephosphorylation activity. From analysis ACP5 and ACP2 concluded that the absence of both of these of membrane fractions from postnuclear supernatants, the ac- enzymes had no effect on the dephosphorylation of endocytosed tivity was enriched most highly in the differential centrifugation arylsulfatase A (14). Thus, the current view is that ACP2 and fraction L, similar to that of lysosomal markers (Fig. S4). ACP5 do not play a significant role in the dephosphorylation of Although these results are consistent with lysosomal localization, lysosomal proteins under physiological conditions. peroxisomes are also enriched in liver L fractions. We therefore In a recent proteomic study of lysosomal proteins in rat tissues, conducted isopycnic centrifugation on liver organelles prepared we made the observation that ACP5 protein was present at low from control mice and mice injected with Triton WR-1339 4 days levels in the brain but relatively high levels in the liver (15). This before subcellular fractionation. Triton WR-1339 induces a finding is consistent with the measurement of a relative abun- lysosomal lipidosis and results in a selective shift in the buoyant dance of ACP5 transcripts in rodents (16). Given that the levels density of lysosomes but not of other organelles. As demon- of ACP5 appeared inversely correlated with levels of glycopro- strated in Fig. S5, the dephosphorylation activity undergoes a teins containing Man-6-P in rat liver and brain, these observa- shift similar to that of lysosomal markers.
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