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Dysregulation of protein modification by ISG15 results in brain cell injury.

UBP43 (USP18) is a protease that removes the ubiquitin-like modifier ISG15 from conjugated proteins. Here we present the first report of dysregulation of protein ISG15 modification by the generation of UBP43 knockout mice. In the absence of UBP43, brain tissue showed an elevated level of ISG15 conjugates, and cellular necrosis was evident in the ependyma. Such disruption of the blood-brain barrier resulted in severe neurologic disorders. These results demonstrate that UBP43 plays a critical role in maintaining the homeostatic balance of ISG15-conjugated protein, and that regulation of cellular levels of ISG15 protein modification is essential for brain cell function.

Pubmed ID: 12208842


  • Ritchie KJ
  • Malakhov MP
  • Hetherington CJ
  • Zhou L
  • Little MT
  • Malakhova OA
  • Sipe JC
  • Orkin SH
  • Zhang DE


Genes & development

Publication Data

September 1, 2002

Associated Grants

  • Agency: NCI NIH HHS, Id: CA79849

Mesh Terms

  • Animals
  • Blood-Brain Barrier
  • Brain
  • Cytokines
  • Endopeptidases
  • Ependyma
  • Gene Expression
  • Hydrocephalus
  • Mice
  • Mice, Knockout
  • Necrosis
  • Phenotype
  • Protein Processing, Post-Translational
  • RNA, Messenger
  • Ubiquitin Thiolesterase
  • Ubiquitins