CLPTM1L is a novel GPI-anchoring pathway component targeted by HCMV

The GPI-anchoring pathway plays important roles in normal development and immune-modulation. MHC Class I Polypeptide-related Sequence A (MICA) is a stress-induced ligand, downregulated by human cytomegalovirus (HCMV) to escape immune recognition. Its most prevalent allele, MICA*008, is expressed as a GPI-anchored protein on the cell surface, via an uncharacterized pathway. Here we identify CLPTM1L (cleft lip and palate transmembrane protein 1-like protein) as a novel GPI-anchoring pathway component, and show that during HCMV infection, US9 downregulates MICA*008 via CLPTM1L. We show that the expression of other GPI-anchored proteins (CD109, CD59, and MELTF) also relies on CLPTM1L, and that like MICA*008, MELTF is downregulated by US9 via CLPTM1L during infection. Mechanistically, we show that CLPTM1L precipitates with the GPI Transamidase Complex (TAC) component PIG-T, and that PIG-T itself is important for the expression of MICA*008 and MELTF. Altogether, we report on a new GPI-anchoring pathway component which is targeted by HCMV.