The E3-Ubiquitin Ligase TRIM50 Interacts with HDAC6 and p62, and Promotes the Sequestration and Clearance of Ubiquitinated Proteins into the Aggresome

PLoS One

Piero Pucci¹  Flora Cozzolino¹  Maria Monti¹  Gerard Didelot²  Alexandre Reymond²  Ester Valentina D’Addetta³  Alessia Calcagnì³  Lucia Micale³  Carmela Fusco³  Bartolomeo Augello³  Giuseppe Merla³  Mikhail Egorov⁴  Roman S. Polishchuk⁴  Andrea Fontana⁵ 

[1] CEINGE Advanced Biotechnology and Department of Organic Chemistry and Biochemistry, Federico II University, Napoli, Italy;Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland;Medical Genetics Unit, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy;Telethon Institute of Genetics and Medicine, Naples, Italy;Unit of biostatistics, IRCCS Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy

关键词: Immunoprecipitation;    Cell staining;    Proteasomes;    HeLa cells;    Autophagic cell death;    Fibroblasts;    Immunoblotting;    Ligases;   

DOI  :  10.1371/journal.pone.0040440

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

In this study we report that, in response to proteasome inhibition, the E3-Ubiquitin ligase TRIM50 localizes to and promotes the recruitment and aggregation of polyubiquitinated proteins to the aggresome. Using Hdac6-deficient mouse embryo fibroblasts (MEF) we show that this localization is mediated by the histone deacetylase 6, HDAC6. Whereas Trim50-deficient MEFs allow pinpointing that the TRIM50 ubiquitin-ligase regulates the clearance of polyubiquitinated proteins localized to the aggresome. Finally we demonstrate that TRIM50 colocalizes, interacts with and increases the level of p62, a multifunctional adaptor protein implicated in various cellular processes including the autophagy clearance of polyubiquitinated protein aggregates. We speculate that when the proteasome activity is impaired, TRIM50 fails to drive its substrates to the proteasome-mediated degradation, and promotes their storage in the aggresome for successive clearance.

【 授权许可】

CC BY