TY - JOUR
T1 - The NKG2D ligand ULBP2 is specifically regulated through an invariant chain-dependent endosomal pathway
AU - Uhlenbrock, Franziska Katharina
AU - Hagemann-Jensen, Michael Henrik
AU - Kehlet, Stephanie
AU - Andresen, Lars
AU - Pastorekova, Silvia
AU - Skov, Søren
N1 - Copyright © 2014 by The American Association of Immunologists, Inc.
PY - 2014/8/15
Y1 - 2014/8/15
N2 - Soluble ULBP2 is a marker for poor prognosis in several types of cancer. In this study we demonstrate that both soluble and cell surface-bound ULBP2 is transported via a so far unrecognized endosomal pathway. ULBP2 surface expression, but not MICA/B, could specifically be targeted and retained by affecting endosomal/lysosomal integrity and protein kinase C activity. The invariant chain was further essential for endosomal transport of ULBP2. This novel pathway was identified through screening experiments by which methylselenic acid was found to possess notable NKG2D ligand regulatory properties. The protein kinase C inhibitor methylselenic acid induced MICA/B surface expression but dominantly blocked ULBP2 surface transport. Remarkably, by targeting this novel pathway we could specifically block the production of soluble ULBP2 from different, primary melanomas. Our findings strongly suggest that the endosomal transport pathway constitutes a novel therapeutic target for ULBP2-producing tumors.
AB - Soluble ULBP2 is a marker for poor prognosis in several types of cancer. In this study we demonstrate that both soluble and cell surface-bound ULBP2 is transported via a so far unrecognized endosomal pathway. ULBP2 surface expression, but not MICA/B, could specifically be targeted and retained by affecting endosomal/lysosomal integrity and protein kinase C activity. The invariant chain was further essential for endosomal transport of ULBP2. This novel pathway was identified through screening experiments by which methylselenic acid was found to possess notable NKG2D ligand regulatory properties. The protein kinase C inhibitor methylselenic acid induced MICA/B surface expression but dominantly blocked ULBP2 surface transport. Remarkably, by targeting this novel pathway we could specifically block the production of soluble ULBP2 from different, primary melanomas. Our findings strongly suggest that the endosomal transport pathway constitutes a novel therapeutic target for ULBP2-producing tumors.
U2 - 10.4049/jimmunol.1303275
DO - 10.4049/jimmunol.1303275
M3 - Journal article
C2 - 25024379
SN - 0022-1767
VL - 193
SP - 1654
EP - 1665
JO - Journal of Immunology
JF - Journal of Immunology
IS - 4
ER -
