Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis.

Abstract

C-type lectins are key players in immune regulation by driving distinct functions of antigen-presenting cells. The C-type lectin CLEC16A gene is located at 16p13, a susceptibility locus for several autoimmune diseases, including multiple sclerosis. However, the function of this gene and its potential contribution to these diseases in humans are poorly understood. In this study, we found a strong upregulation of CLEC16A expression in the white matter of multiple sclerosis patients (n = 14) compared to non-demented controls (n = 11), mainly in perivascular leukocyte infiltrates. Moreover, CLEC16A levels were significantly enhanced in peripheral blood mononuclear cells of multiple sclerosis patients (n = 69) versus healthy controls (n = 46). In peripheral blood mononuclear cells, CLEC16A was most abundant in monocyte-derived dendritic cells, in which it strongly co-localized with human leukocyte antigen class II. Treatment of these professional antigen-presenting cells with vitamin D, a key protective environmental factor in multiple sclerosis, downmodulated CLEC16A in parallel with human leukocyte antigen class II. Knockdown of CLEC16A in distinct types of model and primary antigen-presenting cells resulted in severely impaired cytoplasmic distribution and formation of human leucocyte antigen class II-positive late endosomes, as determined by immunofluorescence and electron microscopy. Mechanistically, CLEC16A participated in the molecular machinery of human leukocyte antigen class II-positive late endosome formation and trafficking to perinuclear regions, involving the dynein motor complex. By performing co-immunoprecipitations, we found that CLEC16A directly binds to two critical members of this complex, RILP and the HOPS complex. CLEC16A silencing in antigen-presenting cells disturbed RILP-mediated recruitment of human leukocyte antigen class II-positive late endosomes to perinuclear regions. Together, we identify CLEC16A as a pivotal gene in multiple sclerosis that serves as a direct regulator of the human leukocyte antigen class II pathway in antigen-presenting cells. These findings are a first step in coupling multiple sclerosis-associated genes to the regulation of the strongest genetic factor in multiple sclerosis, human leukocyte antigen class II.

• Authors: Marvin M van Luijn, Karim L Kreft, Marlieke L Jongsma, Steven W Mes, Annet F Wierenga-Wolf, Marjan van Meurs, Marie-José Melief, Rik van der Kant, Lennert Janssen, Hans Janssen, Rusung Tan, John J Priatel, Jacques Neefjes, Jon D Laman, Rogier Q Hintzen
• Journal: Brain : a journal of neurology (Brain) Vol. 138 Issue Pt 6 Pg. 1531-47 (Jun 2015) ISSN: 1460-2156 [Electronic] England
• PMID: 25823473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: [email protected].

Chemical References

• Adaptor Proteins, Signal Transducing
• CLEC16A protein, human
• Histocompatibility Antigens Class II
• Lectins, C-Type
• Monosaccharide Transport Proteins
• RILP protein, human
• RNA, Small Interfering
• Vitamin D

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Adolescent
• Adult
• Aged
• Antigen-Presenting Cells (drug effects, metabolism)
• Case-Control Studies
• Cells, Cultured
• Dendritic Cells (drug effects, metabolism)
• Endosomes (metabolism)
• Female
• Gene Knockdown Techniques
• Genetic Predisposition to Disease (genetics)
• Histocompatibility Antigens Class II (biosynthesis)
• Humans
• Lectins, C-Type (genetics, physiology)
• Leukocytes, Mononuclear (drug effects, metabolism, ultrastructure)
• Male
• Middle Aged
• Monosaccharide Transport Proteins (genetics, physiology)
• Multiple Sclerosis (genetics)
• Protein Transport (genetics)
• RNA, Small Interfering (pharmacology)
• Up-Regulation (drug effects)
• Vitamin D (pharmacology)
• White Matter (metabolism)
• Young Adult