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Ligand of Numb proteins LNX1p80 and LNX2 interact with the human glycoprotein CD8 alpha and promote its ubiquitylation and endocytosis

D'Agostino, Massimo, Tornillo, Giusy, Caporaso, Maria Gabriella, Barone, Maria Vittoria, Ghigo, Eric, Bonatti, Stefano and Mottola, Giovanna 2011. Ligand of Numb proteins LNX1p80 and LNX2 interact with the human glycoprotein CD8 alpha and promote its ubiquitylation and endocytosis. Journal of Cell Science 124 (21) , pp. 3545-3556. 10.1242/jcs.081224

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Abstract

E3 ubiquitin ligases give specificity to the ubiquitylation process by selectively binding substrates. Recently, their function has emerged as a crucial modulator of T-cell tolerance and immunity. However, substrates, partners and mechanism of action for most E3 ligases remain largely unknown. In this study, we identified the human T-cell co-receptor CD8 α-chain as binding partner of the ligand of Numb proteins X1 (LNX1p80 isoform) and X2 (LNX2). Both LNX mRNAs were found expressed in T cells purified from human blood, and both proteins interacted with CD8α in human HPB-ALL T cells. By using an in vitro assay and a heterologous expression system we showed that the interaction is mediated by the PDZ (PSD95-DlgA-ZO-1) domains of LNX proteins and the cytosolic C-terminal valine motif of CD8α. Moreover, CD8α redistributed LNX1 or LNX2 from the cytosol to the plasma membrane, whereas, remarkably, LNX1 or LNX2 promoted CD8α ubiquitylation, downregulation from the plasma membrane, transport to the lysosomes, and degradation. Our findings highlight the function of LNX proteins as E3 ligases and suggest a mechanism of regulation for CD8α localization at the plasma membrane by ubiquitylation and endocytosis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: The Company of Biologists Ltd
ISSN: 0021-9533
Last Modified: 04 Jun 2017 06:55
URI: http://orca.cf.ac.uk/id/eprint/66226

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