title: Ubiquitination of human leukocyte antigen (HLA)-DM by different membrane-associated RING-CH (MARCH) protein family E3 ligases targets different endocytic pathways.
abstract: HLA-DM plays an essential role in the peptide loading of classical class II molecules and is present both at the cell surface and in late endosomal peptide-loading compartments. Trafficking of DM within antigen-presenting cells is complex and is, in part, controlled by a tyrosine-based targeting signal present in the cytoplasmic tail of DMβ. Here, we show that DM also undergoes post-translational modification through ubiquitination of a single lysine residue present in the cytoplasmic tail of the α chain, DMα. Ubiquitination of DM by MARCH1 and MARCH9 induced loss of DM molecules from the cell surface by a mechanism that cumulatively involved both direct attachment of ubiquitin chains to DMα and a functional tyrosine-based signal on DMβ. In contrast, MARCH8-induced loss of surface DM was entirely dependent upon the tyrosine signal on DMβ. In the absence of this tyrosine residue, levels of DM remained unchanged irrespective of whether DMα was ubiquitinated by MARCH8. The influence of MARCH8 was indirect and may have resulted from modification of components of the endocytic machinery by ubiquitination.
authors.affiliation: Division of Immunology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Jahnke
authors.forename: John
authors.initials: J
authors.lastname: Trowsdale
authors.forename: Adrian P
authors.initials: AP
authors.lastname: Kelly
mesh_terms: D004705:Endocytosis / Q000502:physiology*; D057809:HEK293 Cells; D006681:HLA-D Antigens / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D021382:Protein Sorting Signals / Q000502:physiology*; D017433:Protein Structure, Secondary; D021381:Protein Transport / Q000502:physiology; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D006681:HLA-D Antigens; C084245:HLA-DM antigens; D021382:Protein Sorting Signals; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases