A conserved WW domain-like motif regulates invariant chain-dependent cell-surface transport of the NKG2D ligand ULBP2. Issue 2 (August 2015)

• Record Type: Journal Article
• Authors: Uhlenbrock, Franziska; van Andel, Esther; Andresen, Lars; Skov, Søren
• Is Part Of: Molecular immunology. Volume 66:Issue 2(2015:Aug.)
• Page Start: 418
• Page End: 427
• Publication Date: 2015-08
• Subjects: NKG2D ligands -- ULBP2 -- Invariant chain -- WW domain -- Cell-surface transport; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2015.04.022
• Languages: English
• ISSNs: 0161-5890

Abstract

Highlights: Identification of a WW domain-like motif in the primary protein sequence of NKG2D ligands ULBP1-6 but not in the related MICA/B. The WW domain-like motif is crucial for the cell-surface transport of the NKG2D ligand ULBP2. WW domain-like motif is required for an invariant chain-dependent cell-surface transport of ULBP2. Abstract: Malignant cells expressing NKG2D ligands on their cell surface can be directly sensed and killed by NKG2D-bearing lymphocytes. To ensure this immune recognition, accumulating evidence suggests that NKG2D ligands are trafficed via alternative pathways to the cell surface. We have previously shown that the NKG2D ligand ULBP2 traffics over an invariant chain (Ii)-dependent pathway to the cell surface. This study set out to elucidate how Ii regulates ULBP2 cell-surface transport: We discovered conserved tryptophan (Trp) residues in the primary protein sequence of ULBP1-6 but not in the related MICA/B. Substitution of Trp to alanine resulted in cell-surface inhibition of ULBP2 in different cancer cell lines. Moreover, the mutated ULBP2 constructs were retained and not degraded inside the cell, indicating a crucial role of this conserved Trp-motif in trafficking. Finally, overexpression of Ii increased surface expression of wt ULBP2 while Trp-mutants could not be expressed, proposing that this Trp-motif is required for an Ii-dependent cell-surface transport of ULBP2. Aberrant soluble ULBP2 is immunosuppressive. Thus, targeting a distinct protein module on the ULBP2 sequence could counteract this abnormal expression of ULBP2.