title: Ubiquitin-mediated regulation of CD86 protein expression by the ubiquitin ligase membrane-associated RING-CH-1 (MARCH1).
abstract: The activation of naïve T cells requires antigen presentation by dendritic cells (DCs), and the process of antigen presentation is regulated over the course of DC maturation. One key aspect of this regulation is the cell surface up-regulation upon DC maturation of peptide·MHC-II complexes and the costimulatory molecule CD86. It is now clear that these critical induction events involve changes in ubiquitin-dependent trafficking of MHC-II and CD86 by the E3 ligase membrane-associated RING-CH-1 (MARCH1). Although ubiquitin-dependent trafficking of MHC-II has been well characterized, much less is known regarding the post-transcriptional regulation of CD86 expression. Here, we examined the physical and functional interaction between CD86 and MARCH1. We observed that CD86 is rapidly endocytosed in the presence of MARCH1 followed by lysosome-dependent degradation. Furthermore, we found that the association between CD86 and MARCH1 was conferred primarily by the transmembrane domains of the respective proteins. In contrast to MHC-II, which has a single, conserved ubiquitin acceptor site in the cytosolic domain, we found that multiple lysine residues in the cytosolic tail of CD86 could support ubiquitination consistent with the relative lack of sequence conservation across species within the CD86 cytosolic domain. These findings suggest that MARCH1 recruits multiple substrates via transmembrane domain-mediated interactions to permit substrate ubiquitination in the face of diverse cytosolic domain sequences.
authors: Department of Cellular and Molecular Medicine, University of Arizona, Tucson, Arizona 85721, USA.
authors: Kathleen
authors: K
authors: Corcoran
authors: Maurice
authors: M
authors: Jabbour
authors: Candida
authors: C
authors: Bhagwandin
authors: Martin J
authors: MJ
authors: Deymier
authors: Debra L
authors: DL
authors: Theisen
authors: Lonnie
authors: L
authors: Lybarger
mesh_terms: D000818:Animals; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology*; D008247:Lysosomes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D025801:Ubiquitin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D025801:Ubiquitin; C545340:MARCH1 protein, mouse; D044767:Ubiquitin-Protein Ligases