Phospholipid Scramblase 1 regulates Toll-like receptor 9-mediated type I interferon production in plasmacytoid dendritic cells

Toll-like receptor 9 （TLR9） senses microbial DNA in the endosomes of plasmacytoid dendritic cells （pDCs） and triggers MyD88-dependent type I interferon （IFN） responses. To better understand TLR9 biology in pDCs, we established a yeast two-hybrid library for the identification of TLR9-interacting proteins. Here, we report that an IFN- inducible protein, phospholipid scramblase 1 （PLSCR1）, interacts with TLR9 in pDCs. Knockdown of PLSCR1 expression by siRNA in human pDC cell line led to a 60-70% reduction of IFN-a responses following CpG-ODN （oligodeoxynucleotide） stimulation. Primary pDCs from PLSCRl-deficient mice produced lower amount of type 1 IFN than pDCs from the wild-type mice in response to CpG-ODN, herpes simplex virus and influenza A virus. Following CpG-A stimulation, there were much lower amounts of TLR9 in the early endosomes together with CpG-A in pDCs from PLSCRl-deficient mice. Our study demonstrates that PLSCR1 is a TLR9-interacting protein that plays an important role in pDC＇s type 1 IFN responses by regulating TLR9 trafficking to the endosomal compartment.