Prointerleukin-16 contains a functional CcN motif that regulates nuclear localization

Biochemistry. 2002 Dec 3;41(48):14306-12. doi: 10.1021/bi020163v.

Abstract

The immunomodulatory cytokine interleukin-16 (IL-16) represents the secreted C-terminus of a larger precursor, pro-IL-16. Following cleavage by caspase 3, the residual N-terminal domain translocates into the nucleus, inducing G(0)/G(1) cell cycle arrest. We have previously identified a classical bipartite nuclear localization sequence (NLS) in the N-terminal domain of pro-IL-16. We now show that N-terminal to the NLS domain of pro-IL-16 are protein kinase CK2 substrate and cdc2 kinase substrate sites which, along with the NLS, constitute a dual phosphorylation-regulated CcN motif which regulates nuclear localization of pro-IL-16. In addition, we demonstrate that mutation of either site is associated with impairment of the N-terminal domain's ability to induce G(0)/G(1) cell cycle arrest. This is the first description of a functional CcN motif in a cytokine precursor.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Amino Acid Motifs / genetics
  • Amino Acid Motifs / physiology
  • Amino Acid Sequence
  • Animals
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism
  • COS Cells
  • Casein Kinase II
  • Chlorocebus aethiops
  • G1 Phase / genetics
  • Humans
  • Interleukin-16 / genetics
  • Interleukin-16 / physiology*
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Nuclear Localization Signals / genetics
  • Nuclear Localization Signals / metabolism*
  • Nuclear Localization Signals / physiology
  • Peptide Fragments / genetics
  • Peptide Fragments / physiology
  • Phosphorylation
  • Protein Precursors / genetics
  • Protein Precursors / physiology*
  • Protein Structure, Tertiary / genetics
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Resting Phase, Cell Cycle / genetics
  • Substrate Specificity / genetics
  • Transfection

Substances

  • Interleukin-16
  • Nuclear Localization Signals
  • Peptide Fragments
  • Protein Precursors
  • interleukin 16 precursor
  • Casein Kinase II
  • Protein-Serine-Threonine Kinases
  • CDC2 Protein Kinase