Hirota Y, Hayashi M, Miyauchi Y, Ishii Y, Tanaka Y, Fujimoto K

Lysosome-associated protein transmembrane 4? (LAPTM4?) is a four transmembrane-spanning protein primarily localized in endosomes and lysosomes and has several putative lysosomal targeting signals at its C-terminal cytoplasmic domain, including tyrosine-based motifs (Yxx?) and PY motifs (L/PxxY). LAPTM4? has been previously shown to be ubiquitinated by the E3 ubiquitin ligase Nedd4-1 ...

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through binding to its PY motifs and sorted to lysosomes, however, the molecular mechanisms underlying the localization of LAPTM4? to endosomes/lysosomes have not yet been fully elucidated. In the present study, we show that LAPTM4? binds Nedd4-1 in a manner dependent on PY motifs, while the PY motifs and Nedd4-1 are not necessarily required for LAPTM4? ubiquitination. The binding of LAPTM4? with Nedd4-1, however, is necessary for an effective sorting of LAPTM4? from the Golgi to late endosomes/lysosomes. An unexpected finding is that LAPTM4? is localized in the lumen, but not in the limiting membrane, of late endosomes, and degraded in lysosomes over time. Interestingly, we further found that siRNA knockdown of endosomal sorting complexes required for transport (ESCRT) components that mediate sorting of ubiquitinated membrane proteins into intralumenal vesicles (ILVs) of endosomes selectively blocks the transport of LAPTM4? to endosomes. Collectively, these results suggest that trafficking of LAPTM4? from the Golgi to endosomes is promoted by the interaction with Nedd4-1, which further requires ESCRT components. Furthermore, our findings highlight a novel function for ESCRT proteins in mediating protein and/or vesicle trafficking from the Golgi to endosomes/lysosomes.

Date: Dec. 04, 2020

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