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J Biol Chem. 2011 Sep 16;286(37):32854-65. doi: 10.1074/jbc.M111.255778. Epub 2011 Jul 27.

Neutrophil beta2 integrin inhibition by enhanced interactions of vasodilator-stimulated phosphoprotein with S-nitrosylated actin.

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1
Institute for Environmental Medicine, Department of Emergency Medicine, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104, USA. sthom@mail.med.upenn.edu

Abstract

Production of reactive species in neutrophils exposed to hyperoxia causes S-nitrosylation of β-actin, which increases formation of short actin filaments, leading to alterations in the cytoskeletal network that inhibit β(2) integrin-dependent adherence (Thom, S. R., Bhopale, V. M., Mancini, D. J., and Milovanova, T. N. (2008) J. Biol. Chem. 283, 10822-10834). In this study, we found that vasodilator-stimulated protein (VASP) exhibits high affinity for S-nitrosylated short filamentous actin, which increases actin polymerization. VASP bundles Rac1, Rac2, cyclic AMP-dependent, and cyclic GMP-dependent protein kinases in close proximity to short actin filaments, and subsequent Rac activation increases actin free barbed end formation. Using specific chemical inhibitors or reducing cell concentrations of any of these proteins with small inhibitory RNA abrogates enhanced free barbed end formation, increased actin polymerization, and β(2) integrin inhibition by hyperoxia. Alternatively, incubating neutrophils with formylmethionylleucylphenylalanine or 8-bromo-cyclic GMP activates either cyclic AMP-dependent or cyclic GMP-dependent protein kinase, respectively, outside of the short F-actin pool and phosphorylates VASP on serine 153. Phosphorylated VASP abrogates the augmented polymerization normally observed with S-nitrosylated actin, VASP binding to actin, elevated Rac activity, and elevated formation of actin free barbed ends, thus restoring normal β(2) integrin function.

PMID:
21795685
PMCID:
PMC3173211
DOI:
10.1074/jbc.M111.255778
[Indexed for MEDLINE]
Free PMC Article
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