QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

Vol. 19, Issue 6, 2350-2362, June 2008

This Article Full Text Full Text (PDF) Supplemental Materials All Versions of this Article: E07-11-1189v1 19/6/2350    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pérez-Victoria, F. J. Articles by Bonifacino, J. S. Search for Related Content PubMed PubMed Citation Articles by Pérez-Victoria, F. J. Articles by Bonifacino, J. S.

Requirement of the Human GARP Complex for Mannose 6-phosphate-receptor-dependent Sorting of Cathepsin D to Lysosomes

Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892

Submitted November 29, 2007; Revised February 26, 2008; Accepted March 19, 2008
Monitoring Editor: Jean Gruenberg

The biosynthetic sorting of acid hydrolases to lysosomes relies on transmembrane, mannose 6-phosphate receptors (MPRs) that cycle between the TGN and endosomes. Herein we report that maintenance of this cycling requires the function of the mammalian Golgi-associated retrograde protein (GARP) complex. Depletion of any of the three GARP subunits, Vps52, Vps53, or Vps54, by RNAi impairs sorting of the precursor of the acid hydrolase, cathepsin D, to lysosomes and leads to its secretion into the culture medium. As a consequence, lysosomes become swollen, likely due to a buildup of undegraded materials. Missorting of cathepsin D in GARP-depleted cells results from accumulation of recycling MPRs in a population of light, small vesicles downstream of endosomes. These vesicles might correspond to intermediates in retrograde transport from endosomes to the TGN. Depletion of GARP subunits also blocks the retrograde transport of the TGN protein, TGN46, and the B subunit of Shiga toxin. These observations indicate that the mammalian GARP complex plays a general role in the delivery of retrograde cargo into the TGN. We also report that a Vps54 mutant protein in the Wobbler mouse strain is active in retrograde transport, thus explaining the viability of these mutant mice.

Address correspondence to: Juan S. Bonifacino (juan{at}helix.nih.gov)

Abbreviations used: CatD, cathepsin D; MPR, mannose 6-phosphate receptor; CI-MPR, cation-independent MPR; TGN, trans-Golgi network; GARP, Golgi-associated retrograde protein; Vps, vacuolar protein sorting; STxB, B subunit of Shiga toxin; TEN, tubular endosomal network.

This article has been cited by other articles:

				A. V. Bulankina, A. Deggerich, D. Wenzel, K. Mutenda, J. G. Wittmann, M. G. Rudolph, K. N.J. Burger, and S. Honing TIP47 functions in the biogenesis of lipid droplets J. Cell Biol., May 18, 2009; 185(4): 641 - 655. [Abstract] [Full Text] [PDF]

				Y. Wang, Z. Zhou, C. T. Walsh, and A. P. McMahon Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation PNAS, February 24, 2009; 106(8): 2623 - 2628. [Abstract] [Full Text] [PDF]

				N. Naslavsky, J. McKenzie, N. Altan-Bonnet, D. Sheff, and S. Caplan EHD3 regulates early-endosome-to-Golgi transport and preserves Golgi morphology J. Cell Sci., February 1, 2009; 122(3): 389 - 400. [Abstract] [Full Text] [PDF]