Previous studies have suggested that the prion protein (PrP) functions in cell–cell and cell–matrix adhesions. Although PrP is highly expressed in hematopoietic stem cells and mononuclear leukocytes, its role in the innate immune system remains poorly understood. Here (p. ), Mar Fernandez-Borja and colleagues discovered a novel function for PrP in regulating monocyte migration through modulation of cell adhesion dynamics. Using a stable knockdown (KD) of PrP in human pro-monocytic U937 cells, they observed that PrP is a negative regulator of chemotaxis because PrP KD cells displayed diminished adhesion to β1 integrin ligands and reduced adhesion to the endothelium under flow. In line with this, depletion of PrP resulted in a decreased ability of these cells to form a uropod. Moreover, PrP-KD cells also showed increased motility and diapedesis, as well as a high activity in forming membrane protrusions. Interestingly, the levels of phosphorylated ERM (ezrin–radixin–moesin) proteins, which function in uropod formation, were decreased, suggesting their regulation is affected by PrP. Finally, increased levels of active RhoA and of inactive, phosphorylated cofilin were found in the absence of PrP, which could account for the changes in actin dynamics. On the basis of their results, the authors concluded that PrP regulates integrin-mediated monocyte adhesion and motility through ERM-membrane-cortex adaptors, and modulates actin dynamics through the RhoA-cofilin pathway.
