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LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase

  • 0Genzyme Corporation, 1 Mountain Road, Framingham, MA 01701, USA. david.reczek@genzyme.com
Cell +

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November 21, 2007

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November 21, 2007

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Summary

This summary is machine-generated.

Lysosomal integral membrane protein 2 (LIMP-2) acts as a specific receptor for beta-glucocerebrosidase, independent of the mannose-6-phosphate pathway. LIMP-2 deficiency causes beta-glucocerebrosidase missorting and secretion, impacting Gaucher disease research.

Area Of Science

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background

  • Gaucher disease results from deficient beta-glucocerebrosidase activity.
  • Lysosomal enzyme targeting typically involves the mannose-6-phosphate (M6P) receptor pathway.
  • The M6P-independent lysosomal targeting mechanism for beta-glucocerebrosidase remains unclear.

Purpose Of The Study

  • To identify the specific receptor responsible for the M6P-independent lysosomal trafficking of beta-glucocerebrosidase.
  • To elucidate the interaction between beta-glucocerebrosidase and its putative receptor.

Main Methods

  • Affinity chromatography to identify binding partners of beta-glucocerebrosidase.
  • Analysis of LIMP-2 deficient mouse tissues, fibroblasts, and macrophages.
  • Biochemical assays to measure beta-glucocerebrosidase activity and protein levels.
  • In vivo studies using mouse sera and in vitro complementation assays.

Main Results

  • Lysosomal integral membrane protein 2 (LIMP-2) was identified as a specific binding partner for beta-glucocerebrosidase.
  • LIMP-2 deficiency in mice led to severely decreased beta-glucocerebrosidase levels and activity in tissues.
  • Beta-glucocerebrosidase was predominantly secreted in LIMP-2 deficient cells and found at higher levels in sera.
  • Reconstitution of LIMP-2 rescued beta-glucocerebrosidase levels and corrected the trafficking of a mutant form.

Conclusions

  • LIMP-2 functions as a specific, M6P-independent receptor for beta-glucocerebrosidase.
  • This interaction is crucial for proper lysosomal targeting and retention of beta-glucocerebrosidase.
  • Findings provide insights into Gaucher disease pathogenesis and potential therapeutic strategies.

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