title: Membrane Oxidation Enables the Cytosolic Entry of Polyarginine Cell-penetrating Peptides.
abstract: Arginine-rich peptides can penetrate cells and consequently be used as delivery agents in various cellular applications. The activity of these reagents is often context-dependent, and the parameters that impact cell entry are not fully understood, giving rise to variability and limiting progress toward their usage. Herein, we report that the cytosolic penetration of linear polyarginine peptides is dependent on the oxidation state of the cell. In particular, we find that hypoxia and cellular antioxidants inhibit cell penetration. In contrast, oxidants promote cytosolic cell entry with an efficiency proportional to the level of reactive oxygen species generated within membranes. Moreover, an antibody that binds to oxidized lipids inhibits cell penetration, whereas extracellularly administered pure oxidized lipids enhance peptide transport into cells. Overall, these data indicate that oxidized lipids are capable of mediating the transport of polyarginine peptides across membranes. These data may also explain variability in cell-penetrating peptide performance in different experimental conditions. These new findings therefore provide new opportunities for the rational design of future cell-permeable compounds and for the optimization of delivery protocols.
authors.affiliation: From the Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128.
authors.forename: Ting-Yi
authors.initials: TY
authors.lastname: Wang
authors.affiliation: From the Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128.
authors.forename: Yusha
authors.initials: Y
authors.lastname: Sun
authors.affiliation: From the Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128.
authors.forename: Nandhini
authors.initials: N
authors.lastname: Muthukrishnan
authors.affiliation: From the Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Erazo-Oliveras
authors.affiliation: From the Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128.
authors.forename: Kristina
authors.initials: K
authors.lastname: Najjar
authors.affiliation: From the Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843-2128 pellois@tamu.edu.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pellois
mesh_terms: D001692:Biological Transport; D018929:Cell Culture Techniques; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D057846:Cell-Penetrating Peptides / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010455:Peptides / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D057846:Cell-Penetrating Peptides; D008563:Membrane Lipids; D010455:Peptides; D017382:Reactive Oxygen Species; C015462:polyarginine
keywords: cell culture; cell-penetrating peptide (CPP); oxidation-reduction (redox); peptide transport; plasma membrane