WIP is a chaperone for Wiskott-Aldrich syndrome protein (WASP)

Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):926-31. doi: 10.1073/pnas.0610275104. Epub 2007 Jan 9.

Abstract

Wiskott-Aldrich syndrome protein (WASP) is in a complex with WASP-interacting protein (WIP). WASP levels, but not mRNA levels, were severely diminished in T cells from WIP(-/-) mice and were increased by introduction of WIP in these cells. The WASP binding domain of WIP was shown to protect WASP from degradation by calpain in vitro. Treatment with the proteasome inhibitors MG132 and bortezomib increased WASP levels in T cells from WIP(-/-) mice and in T and B lymphocytes from two WAS patients with missense mutations (R86H and T45M) that disrupt WIP binding. The calpain inhibitor calpeptin increased WASP levels in activated T and B cells from the WASP patients, but not in primary T cells from the patients or from WIP(-/-) mice. Despite its ability to increase WASP levels proteasome inhibition did not correct the impaired IL-2 gene expression and low F-actin content in T cells from the R86H WAS patient. These results demonstrate that WIP stabilizes WASP and suggest that it may also be important for its function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Arginine / genetics
  • Arginine / metabolism
  • Boronic Acids / pharmacology
  • Bortezomib
  • Calpain / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cytoskeletal Proteins
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Interleukin-2 / biosynthesis
  • Intracellular Signaling Peptides and Proteins
  • Jurkat Cells
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism*
  • Mutation, Missense / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Protein Binding
  • Pyrazines / pharmacology
  • Wiskott-Aldrich Syndrome / genetics
  • Wiskott-Aldrich Syndrome / metabolism*
  • Wiskott-Aldrich Syndrome Protein / metabolism*

Substances

  • Actins
  • Boronic Acids
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Enzyme Inhibitors
  • Interleukin-2
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • Proteasome Inhibitors
  • Pyrazines
  • WIPF1 protein, human
  • Waspip protein, mouse
  • Wiskott-Aldrich Syndrome Protein
  • Bortezomib
  • Arginine
  • Calpain
  • Proteasome Endopeptidase Complex