Monoubiquitination of survival motor neuron regulates its cellular localization and Cajal body integrity

Ke Jun Han, Daniel Foster, Edward W. Harhaj, Monika Dzieciatkowska, Kirk Hansen, Chang Wei Liu

Research output: Research - peer-reviewArticle

Abstract

Low levels of the survival motor neuron (SMN) protein cause spinal muscular atrophy, the leading genetic disorder for infant mortality. SMN is ubiquitously expressed in various cell types and localizes in both the cytoplasm and the nucleus, where it concentrates in two subnuclear structures termed Cajal body (CB) and gems. In addition, SMN can also be detected in the nucleolus of neurons. Mechanisms that control SMN sorting in the cell remain largely unknown. Here, we report that the ubiquitin (Ub) ligase Itch directly interacts with and monoubiquitinates SMN. Monoubiquitination of SMN has a mild effect on promoting proteasomal degradation of SMN. We generated two SMN mutants, SMN(K0), in which all lysines are mutated to arginines and thereby abolishing SMN ubiquitination, and Ub-SMN(K0), in which a single Ub moiety is fused at the N-terminus of SMN(K0) and thereby mimickingSMNmonoubiquitination. Immunostaining assays showed that SMN(K0) mainly localizes in the nucleus, whereas Ub-SMN(K0) localizes in both the cytoplasm and the nucleolus in neuronal SH-SY5Y cells. Interestingly, canonical CB foci and coilin/small nuclear ribonucleoprotein (snRNP) co-localization are significantly impaired in SH-SY5Y cells stably expressing SMN(K0) or Ub-SMN(K0). Thus, our studies discover that Itch monoubiquitinates SMN and monoubiquitination of SMN plays an important role in regulating its cellular localization. Moreover, mislocalization of SMN disrupts CB integrity and likely impairs snRNP maturation.

LanguageEnglish (US)
Article numberddw021
Pages1392-1405
Number of pages14
JournalHuman Molecular Genetics
Volume25
Issue number7
DOIs
StatePublished - Apr 1 2016

Fingerprint

Motor Neurons
Ubiquitin
Small Nuclear Ribonucleoproteins
Cytoplasm
Spinal Muscular Atrophy
Inborn Genetic Diseases
Ubiquitination
Infant Mortality
Ligases
Lysine
Arginine
Neurons
Proteins

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Han, K. J., Foster, D., Harhaj, E. W., Dzieciatkowska, M., Hansen, K., & Liu, C. W. (2016). Monoubiquitination of survival motor neuron regulates its cellular localization and Cajal body integrity. Human Molecular Genetics, 25(7), 1392-1405. [ddw021]. DOI: 10.1093/hmg/ddw021

Monoubiquitination of survival motor neuron regulates its cellular localization and Cajal body integrity. / Han, Ke Jun; Foster, Daniel; Harhaj, Edward W.; Dzieciatkowska, Monika; Hansen, Kirk; Liu, Chang Wei.

In: Human Molecular Genetics, Vol. 25, No. 7, ddw021, 01.04.2016, p. 1392-1405.

Research output: Research - peer-reviewArticle

Han, KJ, Foster, D, Harhaj, EW, Dzieciatkowska, M, Hansen, K & Liu, CW 2016, 'Monoubiquitination of survival motor neuron regulates its cellular localization and Cajal body integrity' Human Molecular Genetics, vol 25, no. 7, ddw021, pp. 1392-1405. DOI: 10.1093/hmg/ddw021
Han KJ, Foster D, Harhaj EW, Dzieciatkowska M, Hansen K, Liu CW. Monoubiquitination of survival motor neuron regulates its cellular localization and Cajal body integrity. Human Molecular Genetics. 2016 Apr 1;25(7):1392-1405. ddw021. Available from, DOI: 10.1093/hmg/ddw021
Han, Ke Jun ; Foster, Daniel ; Harhaj, Edward W. ; Dzieciatkowska, Monika ; Hansen, Kirk ; Liu, Chang Wei. / Monoubiquitination of survival motor neuron regulates its cellular localization and Cajal body integrity. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 7. pp. 1392-1405
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