Mannose 6-phosphate-independent Lysosomal Sorting of Limp-2

Blanz J, Zunke F, Markmann S, Damme M, Braulke T, Saftig P, Schwake M (2015)
Traffic 16(10): 1127-1136.

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The lysosomal integral membrane protein type 2 (LIMP-2/SCARB2) has been described as a mannose 6-phosphate (M6P)-independent trafficking receptor for beta-glucocerebrosidase (GC). Recently, a putative M6P residue in a crystal structure of a recombinantly expressed LIMP-2 ectodomain has been reported. Based on surface plasmon resonance and fluorescence lifetime imaging analyses, it was suggested that the interaction of soluble LIMP-2 with the cation-independent M6P receptor (MPR) results in M6P-dependent targeting of LIMP-2 to lysosomes. As the physiological relevance of this observation was not addressed, we investigated M6P-dependent delivery of LIMP-2 to lysosomes in murine liver and mouse embryonic fibroblasts. We demonstrate that LIMP-2 and GC reach lysosomes independent of the M6P pathway. In fibroblasts lacking either MPRs or the M6P-forming N-acetylglucosamine (GlcNAc)-1-phosphotransferase, LIMP-2 still localizes to lysosomes. Immunoblot analyses also revealed comparable LIMP-2 levels within lysosomes purified from liver of wild-type (wt) and GlcNAc-1-phosphotransferase-defective mice. Heterologous expression of the luminal domain of LIMP-2 in wild-type, LIMP-2-deficient and GlcNAc-1-phosphotransferase-defective cells further established that the M6P modification is dispensable for lysosomal sorting of LIMP-2. Finally, cathepsin Z, a known GlcNAc-1-phosphotransferase substrate, but not LIMP-2, could be precipitated with M6P-specific antibodies. These data prove M6P-independent lysosomal sorting of LIMP-2 and subsequently GC in vivo.
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Blanz J, Zunke F, Markmann S, et al. Mannose 6-phosphate-independent Lysosomal Sorting of Limp-2. Traffic. 2015;16(10):1127-1136.
Blanz, J., Zunke, F., Markmann, S., Damme, M., Braulke, T., Saftig, P., & Schwake, M. (2015). Mannose 6-phosphate-independent Lysosomal Sorting of Limp-2. Traffic, 16(10), 1127-1136. doi:10.1111/tra.12313
Blanz, J., Zunke, F., Markmann, S., Damme, M., Braulke, T., Saftig, P., and Schwake, M. (2015). Mannose 6-phosphate-independent Lysosomal Sorting of Limp-2. Traffic 16, 1127-1136.
Blanz, J., et al., 2015. Mannose 6-phosphate-independent Lysosomal Sorting of Limp-2. Traffic, 16(10), p 1127-1136.
J. Blanz, et al., “Mannose 6-phosphate-independent Lysosomal Sorting of Limp-2”, Traffic, vol. 16, 2015, pp. 1127-1136.
Blanz, J., Zunke, F., Markmann, S., Damme, M., Braulke, T., Saftig, P., Schwake, M.: Mannose 6-phosphate-independent Lysosomal Sorting of Limp-2. Traffic. 16, 1127-1136 (2015).
Blanz, Judith, Zunke, Friederike, Markmann, Sandra, Damme, Markus, Braulke, Thomas, Saftig, Paul, and Schwake, Michael. “Mannose 6-phosphate-independent Lysosomal Sorting of Limp-2”. Traffic 16.10 (2015): 1127-1136.
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