title: N-WASP inhibitor wiskostatin nonselectively perturbs membrane transport by decreasing cellular ATP levels.
abstract: Wiskott-Aldrich syndrome protein (WASP) and WAVE stimulate actin-related protein (Arp)2/3-mediated actin polymerization, leading to diverse downstream effects, including the formation and remodeling of cell surface protrusions, modulation of cell migration, and intracytoplasmic propulsion of organelles and pathogens. Selective inhibitors of individual Arp2/3 activators would enable more exact dissection of WASP- and WAVE-dependent cellular pathways and are potential therapeutic targets for viral pathogenesis. Wiskostatin is a recently described chemical inhibitor that selectively inhibits neuronal WASP (N-WASP)-mediated actin polymerization in vitro. A growing number of recent studies have utilized this drug in vivo to uncover novel cellular functions for N-WASP; however, the selectivity of wiskostatin in intact cells has not been carefully explored. In our studies with this drug, we observed rapid and dose-dependent inhibition of N-WASP-dependent membrane trafficking steps. Additionally, however, we found that addition of wiskostatin inhibited numerous other cellular functions that are not believed to be N-WASP dependent. Further studies revealed that wiskostatin treatment caused a rapid, profound, and irreversible decrease in cellular ATP levels, consistent with its global effects on cell function. Our data caution against the use of this drug as a selective perturbant of N-WASP-dependent actin dynamics in vivo.
authors.affiliation: Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Guerriero
authors.forename: Ora A
authors.initials: OA
authors.lastname: Weisz
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000037:antagonists & inhibitors / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active; D002227:Carbazoles / Q000494:pharmacology*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D004285:Dogs; D007424:Intracellular Fluid / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D002227:Carbazoles; D011412:Propanolamines; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; C489942:wiskostatin; D000255:Adenosine Triphosphate