Structural Determinants Involved in the Regulation of CXCL14/BRAK Expression by the 26 S Proteasome

Francis C. Peterson, Jeffery A. Thorpe, Adam G. Harder, Brian F. Volkman, Steven R. Schwarze

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

The chemokine CXCL14/BRAK participates in immune surveillance by recruiting dendritic cells. CXCL14 gene expression is altered in a number of cancers, but protein expression levels have not been investigated. Here we report that CXCL14 protein can be expressed in primary epithelial cells; however, in several immortalized and cancer cell lines this protein is targeted for polyubiquitylation and proteasomal degradation. We determined the NMR structure of CXCL14 to identify motifs controlling its expression. CXCL14 adopts the canonical chemokine tertiary fold but contains a unique five amino acid insertion (41VSRYR45) relative to other CXC chemokines. Deletion or substitution of key residues within this insertion prevented proteasomal degradation. Furthermore, we defined a 15 amino acid fragment of CXCL14 that is sufficient to induce proteasomal degradation. This study elucidates a post-translational mechanism for the loss of CXCL14 in cancer and a novel mode of chemokine regulation.

Original languageEnglish
Pages (from-to)813-822
Number of pages10
JournalJournal of Molecular Biology
Volume363
Issue number4
DOIs
StatePublished - Nov 3 2006

Bibliographical note

Funding Information:
We thank Dr Rolf Jakobi for providing the pEXPRESS GFP plasmid. This work was supported in part by NIH grant AI058072 (to B.F.V.).

Keywords

  • CXCL14
  • NMR spectroscopy
  • cancer
  • chemokine
  • proteasome

ASJC Scopus subject areas

  • Molecular Biology
  • Biophysics
  • Structural Biology

Fingerprint

Dive into the research topics of 'Structural Determinants Involved in the Regulation of CXCL14/BRAK Expression by the 26 S Proteasome'. Together they form a unique fingerprint.

Cite this