Journal
DEVELOPMENTAL CELL
Volume 10, Issue 3, Pages 343-354Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2006.01.012
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Funding
- NCI NIH HHS [T32 CA009140, T32-CA-029141] Funding Source: Medline
- NEI NIH HHS [R01 EY015625] Funding Source: Medline
- NIAMS NIH HHS [R01 AR048155, R01 AR 041855] Funding Source: Medline
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Cargo partitioning into intralumenal vesicles (ILVs) of multivesicular endosomes underlies such cellular processes as receptor downregulation, viral budding, and blogenesis of lysosome-related organelles such as melanosomes. We show that the melanosomal protein Pmel17 is sorted into ILVs by a mechanism that is dependent upon lumenal determinants and conserved in nonpigment cells. Pmel17 targeting to ILVs does not require its native cytoplasmic domain or cytoplasmic residues targeted by ubiquitylation and, unlike sorting of ubiquitylated cargo, is insensitive to functional inhibition of Hrs and ESCRT complexes. Chimeric protein and deletion analyses indicate that two N-terminal lumenal subdomains are necessary and sufficient for ILV targeting. Pmel17fibril formation, which occurs during melanosome maturation in melanocytes, requires a third lumenal subdomain and proteolytic processing that itself requires ILV localization. These results establish an Hrs- and perhaps ESCRT-independent pathway of ILV sorting by lumenal determinants and a requirement for ILV sorting in fibril formation.
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