Ubiquitination of the N-terminal region of caveolin-1 regulates endosomal sorting by VCP/p97.

Caveolin-1 (CAV1) is the defining constituent of caveolae at the plasma membrane of many mammalian cells. For turnover, CAV1 is ubiquitinated and sorted to late endosomes and lysosomes. Sorting of CAV1 requires the AAA+-type ATPase VCP and its cofactor UBXD1. However, it is unclear in which region CAV1 is ubiquitinated ...
and how ubiquitination is linked to sorting of CAV1 by VCP-UBXD1. Here, we show through site-directed mutagenesis that ubiquitination of CAV1 occurs at any of the 6 lysine residues 5,26,30,39,47 and 57 that are clustered in the N-terminal region, but not at lysines in the oligomerization, intra-membrane or C-terminal domains. Mutation of K5-57 to arginines prevented binding of the VCP-UBXD1 complex and, importantly, strongly reduced recruitment of VCP-UBXD1 to endocytic compartments. Moreover, K5-57R mutation specifically interfered with trafficking of CAV1 from early to late endosomes. Conversely and consistently, depletion of VCP or UBXD1 led to accumulation of ubiquitinated CAV1, suggesting that VCP acts downstream of ubiquitination and is required for transport of the ubiquitinated form of CAV1 to late endosomes. These results define the N-terminal region of CAV1 as the critical ubiquitin conjugation site, and, together with previous data, demonstrate the significance of this ubiquitination for binding to the VCP-UBXD1 complex and for sorting into lysosomes.
J. Biol. Chem.
Date: Jan. 19, 2013
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