CXCR4 Stimulates Macropinocytosis: Implications for Cellular Uptake of Arginine-Rich Cell-Penetrating Peptides and HIV

SummaryCXCR4 is a coreceptor of HIV-1 infection in host cells. Through a photocrosslinking study to identify receptors involved in internalization of oligoarginine cell-penetrating peptides (CPPs), we found that CXCR4 serves as a receptor that stimulates macropinocytic uptake of the arginine 12-mer peptide (R12) but not of the 8-mer. We also found that stimulating CXCR4 with its intrinsic ligands, stromal cell-derived factor 1α and HIV-1 envelope glycoprotein 120, induced macropinocytosis. R12 had activity to prevent viral infection for HIV-1IIIB, a subtype of HIV-1 that uses CXCR4 as a coreceptor for entry into susceptible cells, whereas the addition of a macropinocytosis inhibitor, dimethylamiloride, resulted in enhancement of viral infection. The present study shows that CXCR4 triggers macropinocytosis, which may have implications for the cellular uptake of oligoarginine CPPs and internalization of HIV.

Graphical AbstractFigure optionsDownload high-quality image (260 K)Download as PowerPoint slideHighlights
► CXCR4 was identified as a receptor to stimulate cellular uptake of R12 peptide
► Interaction with R12 stimulates internalization of CXCR4 via macropinocytosis
► SDF-1α and HIV-1 gp120 protein also induce macropinocytosis
► Macropinocytic uptake of HIV-1 diminished the infection of host cells