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Ufd2, a novel autoantigen in scleroderma, regulates sister chromatid separation.

The characterization of molecules recognized by patients with autoimmune diseases has provided significant insights into important biological pathways. In these studies, we define Ufd2 (a novel E4 polyubiquitylating enzyme) as a new autoantigen in scleroderma, and show that it regulates chromosome condensation and separation during mitosis in human cells. Ufd2 is regulated by phosphorylation in mitosis. Inhibition of Ufd2 expression results in mitotic arrest at the metaphase-anaphase transition, where cells manifest abnormal chromosome morphology, missegregated chromosomes, irregular spindles, and premature separation of sister chromatids. This is accompanied by premature separase activation, and accumulation of securin in a novel modified form. We further demonstrate that Ufd2 directly and efficiently ubiquitylates securin in vitro and is required for securin polyubiquitylation in vivo. This is the first description of a physiologic substrate for Ufd2, establishing this E4 enzyme as an important regulator of chromosome condensation and separation during mitosis in human cells. Its targeting in scleroderma, together with many other components of the mitotic machinery, reinforces the concept that mitotic cells may be an important focus of the autoimmune response in this disease.

Pubmed ID: 15611659

Authors

  • Spinette S
  • Lengauer C
  • Mahoney JA
  • Jallepalli PV
  • Wang Z
  • Casciola-Rosen L
  • Rosen A

Journal

Cell cycle (Georgetown, Tex.)

Publication Data

December 1, 2004

Associated Grants

  • Agency: NIAMS NIH HHS, Id: AR-44684
  • Agency: NIDCR NIH HHS, Id: DE-12354
  • Agency: NHLBI NIH HHS, Id: HL-56091

Mesh Terms

  • Apoptosis
  • Autoantibodies
  • Autoantigens
  • Case-Control Studies
  • Cell Cycle Proteins
  • Chromatids
  • Chromosome Segregation
  • Endopeptidases
  • Epithelial Cells
  • Gene Expression Regulation
  • HeLa Cells
  • Humans
  • In Situ Hybridization, Fluorescence
  • K562 Cells
  • Mitosis
  • Neoplasm Proteins
  • Nocodazole
  • Phosphorylation
  • RNA, Small Interfering
  • Scleroderma, Systemic
  • Securin
  • Separase
  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligase Complexes