Burana D, Yoshihara H, Tanno H, Yamamoto A, Saeki Y, Tanaka K, Komada M

Caveolin-1 (Cav-1) is an oligomeric protein that forms flask-shaped lipid-rich pits, termed caveolae, on the plasma membrane. Cav-1 is targeted for lysosomal degradation in ubiquitination- and VCP-dependent manners. VCP, an AAA-type ATPase that remodels or segregates ubiquitinated protein complexes, has been proposed to disassemble Cav-1 oligomers on the endosomal membrane, ...

Read More

thereby facilitating the trafficking of Cav-1 to the lysosome. Genetic mutations in VCP compromise the lysosomal trafficking of Cav-1, leading to a disease called inclusion body myopathy, Paget's disease of the bone and frontotemporal dementia (IBMPFD). We herein identified the Ankrd13 family of ubiquitin-interacting motif (UIM)-containing proteins as novel VCP-interacting molecules on the endosome. Ankrd13 proteins formed a ternary complex with VCP and Cav-1, and exhibited high binding affinity to ubiquitinated Cav-1 oligomers in a UIM-dependent manner. Mass spectrometric analyses revealed that Cav-1 undergoes Lys63-linked polyubiquitination, which serves as a lysosomal trafficking signal, and that the UIMs of Ankrd13 proteins bind preferentially to this ubiquitin chain type. The overexpression of Ankrd13 caused enlarged hollow late endosomes, which was reminiscent of the phenotype of the VCP mutations in IBMPFD. The overexpression of Ankrd13 proteins also stabilized ubiquitinated Cav-1 oligomers on the limiting membrane of enlarged endosomes. The interaction with Ankrd13 was abrogated in IMBPFD-associated VCP mutants. Collectively, our results suggest that Ankrd13 proteins cooperate with VCP to regulate the lysosomal trafficking of ubiquitinated Cav-1.

Date: Jan. 21, 2016

View in: Pubmed Google Scholar

190861