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.

Characterization of the Mammalian CORVET and HOPS Complexes and Their Modular Restructuring for Endosome Specificity

“…The organization of these mammalian complexes has only partly been addressed with seemingly conflicting results and hampered the interpretation of functional experiments in which the roles of specific or multiple units are addressed (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Furthermore, it is not known what drives membrane specificity of these complexes in mammals.…”

Elucidating the Molecular Basis of Multiple Sclerosis and Understanding the Disease Pathophysiology

“…This molecule has been recently found to regulate the pathway of MHC class II endosome formation and trafficking in DC [16].…”

“…More so, vitamin D/ VDR regulate the transcription of the HLA-DRB1*15 allele and several other non-HLA MS susceptibility loci [26][27][28][29]. In addition, vitamin D can downregulate CLEC16A, consequently suppressing MHC class II expression [16]. Also, VDR regulates the cathelicidin antimicrobial peptide (CAMP), which induces the expression of cathelicidin LL-37.…”

From genetic associations to functional studies in multiple sclerosis

“…To explore the role of the MS‐associated CLEC16A in HLA‐II antigen presentation, van Luijn et al . used a melanoma MelJuSo cell line, where CLEC16A expression was knocked down after CLEC16A‐specific small‐interfering RNA (siRNA) transfection. They found that CLEC16A knockdown impaired the biogenesis of HLA class II‐positive late endosomal compartments.…”