Internalizing MHC class II-peptide complexes are ubiquitinated in early endosomes and targeted for lysosomal degradation

Kazuyuki Furuta, Even Walseng, Paul A. Roche

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

As sentinels of the immune system, dendritic cells (DCs) continuously generate and turnover antigenic peptide-MHC class II complexes (pMHC-II). pMHC-II generation is a complex process that involves many well-characterized MHC-II biosynthetic intermediates; however, the mechanisms leading to MHC-II turnover/degradation are poorly understood. We now show that pMHC-II complexes undergoing clathrin-independent endocytosis from the DC surface are efficiently ubiquitinated by the E3 ubiquitin ligase March-I in early endosomes, whereas biosynthetically immature MHC-II-Invariant chain (Ii) complexes are not. The inability of MHC-II-Ii to serve as a March-I substrate is a consequence of Ii sorting motifs that divert the MHC-II-Ii complex away from March-I+ early endosomes. When these sorting motifs are mutated, or when clathrin-mediated endocytosis is inhibited, MHC-II-Ii complexes internalize by using a clathrin-independent endocytosis pathway and are now ubiquitinated as efficiently as pMHC-II complexes. These data show that the selective ubiquitination of internalizing surface pMHC-II in March-I+ early endosomes promotes degradation of "old" pMHC-II and spares forms of MHC-II that have not yet loaded antigenic peptides or have not yet reached the DC surface.

Original languageEnglish
Pages (from-to)20188-20193
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number50
DOIs
Publication statusPublished - Dec 10 2013
Externally publishedYes

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