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Published 20 November 2006. doi:10.1083/jcb.200603001
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 4, 631-645
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Article

 Transport of LAPTM5 to lysosomes requires association with the ubiquitin ligase Nedd4, but not LAPTM5 ubiquitination

Youngshil Pak1,2, Wioletta K. Glowacka1,2, M. Christine Bruce1,2, Nam Pham1,2, and Daniela Rotin1,2

1 Program in Cell Biology, The Hospital for Sick Children, and 2 Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada, M5G 1X8

Correspondence to Daniela Rotin: drotin{at}sickkids.ca

LAPTM5 is a lysosomal transmembrane protein expressed in immune cells. We show that LAPTM5 binds the ubiquitin-ligase Nedd4 and GGA3 to promote LAPTM5 sorting from the Golgi to the lysosome, an event that is independent of LAPTM5 ubiquitination. LAPTM5 contains three PY motifs (L/PPxY), which bind Nedd4-WW domains, and a ubiquitin-interacting motif (UIM) motif. The Nedd4–LAPTM5 complex recruits ubiquitinated GGA3, which binds the LAPTM5-UIM; this interaction does not require the GGA3-GAT domain. LAPTM5 mutated in its Nedd4-binding sites (PY motifs) or its UIM is retained in the Golgi, as is LAPTM5 expressed in cells in which Nedd4 or GGA3 is knocked-down with RNAi. However, ubiquitination-impaired LAPTM5 can still traffic to the lysosome, suggesting that Nedd4 binding to LAPTM5, not LAPTM5 ubiquitination, is required for targeting. Interestingly, Nedd4 is also able to ubiquitinate GGA3. These results demonstrate a novel mechanism by which the ubiquitin-ligase Nedd4, via interactions with GGA3 and cargo (LAPTM5), regulates cargo trafficking to the lysosome without requiring cargo ubiquitination.

Y. Pak and W.K. Glowacka contributed equally to this paper.

Abbreviations used in this paper: HEK, human embryonic kidney; IP, immunoprecipitation; LAPTM, lysosomal-associated protein transmembrane; LE, late endosome; MVB, multivesicular body; Pm, plasma membrane; TM, transmembrane; UIM, ubiquitin-interacting motif; WT, wild type.


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