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Proc Natl Acad Sci U S A. 2011 Jun 14;108(24):9933-8. doi: 10.1073/pnas.1102397108. Epub 2011 May 31.

Mannose receptor polyubiquitination regulates endosomal recruitment of p97 and cytosolic antigen translocation for cross-presentation.

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1
Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany.

Abstract

The molecular mechanisms regulating noncanonical protein transport across cellular membranes are poorly understood. Cross-presentation of exogenous antigens on MHC I molecules by dendritic cells (DCs) generally requires antigen translocation from the endosomal compartment into the cytosol for proteasomal degradation. In this study, we demonstrate that such translocation is controlled by the endocytic receptor and regulated by ubiquitination. Antigens internalized by the mannose receptor (MR), an endocytic receptor that targets its ligands specifically toward cross-presentation, were translocated into the cytosol only after attachment of a lysin48-linked polyubiquitin chain to the cytosolic region of the MR. Furthermore, we identify TSG101 as a central regulator of MR ubiquitination and antigen translocation. Importantly, we demonstrate that MR polyubiquitination mediates the recruitment of p97, a member of the ER-associated degradation machinery that provides the driving force for antigen translocation, toward the endosomal membrane, proving the central role of the endocytic receptor and its ubiquitination in antigen translocation.

PMID:
21628571
PMCID:
PMC3116392
DOI:
10.1073/pnas.1102397108
[Indexed for MEDLINE]
Free PMC Article

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