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

Sarah Spinette, Christoph Lengauer, James A. Mahoney, Prasad V. Jallepalli, Zhenghe Wang, Livia Casciola-Rosen, Antony Rosen

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1612-1618
Number of pages7
JournalCell Cycle
Volume3
Issue number12
StatePublished - Dec 2004

Keywords

  • Autoantigen
  • Mitosis
  • Securin
  • Ubiquitylation
  • Ufd2

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Spinette, S., Lengauer, C., Mahoney, J. A., Jallepalli, P. V., Wang, Z., Casciola-Rosen, L., & Rosen, A. (2004). Ufd2, a novel autoantigen in scleroderma, regulates sister chromatid separation. Cell Cycle, 3(12), 1612-1618.