The cleavage of HuR interferes with its transportin-2-mediated nuclear import and promotes muscle fiber formation

P. Beauchamp, C. Nassif, S. Hillock, K. Van Der Giessen, C. Von Roretz, B. J. Jasmin, Imed Gallouzi

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Although the function of posttranscriptional processes in regulating the expression of genes involved in muscle fiber formation (myogenesis) is well accepted, the mechanisms by which these effects are mediated remain elusive. Here, we uncover such a mechanism and show that during myogenesis, a fraction of the posttranscriptional regulator human antigen R (HuR) is cleaved in a caspase-dependent manner in both cell culture and animal models. Disruption of caspase activity in cultured myoblasts or knocking out the caspase-3 gene in mice significantly reduced HuR cleavage and the cytoplasmic accumulation of HuR in muscle fibers. The non-cleavable isoform of HuR, HuRD226A, failed to reestablish the myogenic potential of HuR-depleted myoblasts. HuR cleavage generates two fragments: HuR-cleavage product 1 (HuR-CP1) (24 kDa) and HuR-CP2 (8 kDa). Here, we show that one of these fragments (HuR-CP1) binds to the HuR import factor transportin-2 (TRN2) allowing HuR to accumulate in the cytoplasm. As this cytoplasmic accumulation is required for the promyogenic function of HuR, our data support a model, whereby during the transition phase from myoblasts to myotubes, a proportion of HuR is cleaved to generate HuR-CP1. By interfering with the TRN2-mediated import of HuR, this CP helps non-cleaved HuR accumulate in the cytoplasm thus promoting myogenesis.

Original languageEnglish
Pages (from-to)1588-1599
Number of pages12
JournalCell Death and Differentiation
Volume17
Issue number10
DOIs
Publication statusPublished - Oct 2010
Externally publishedYes

Fingerprint

Karyopherins
Cell Nucleus Active Transport
Antigens
Muscles
Muscle Development
Myoblasts
Caspases
Cytoplasm
R Factors

Keywords

  • caspases
  • HuR
  • mRNA stability
  • muscle cell differentiation
  • protein import
  • transportin-2

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

The cleavage of HuR interferes with its transportin-2-mediated nuclear import and promotes muscle fiber formation. / Beauchamp, P.; Nassif, C.; Hillock, S.; Van Der Giessen, K.; Von Roretz, C.; Jasmin, B. J.; Gallouzi, Imed.

In: Cell Death and Differentiation, Vol. 17, No. 10, 10.2010, p. 1588-1599.

Research output: Contribution to journalArticle

Beauchamp, P. ; Nassif, C. ; Hillock, S. ; Van Der Giessen, K. ; Von Roretz, C. ; Jasmin, B. J. ; Gallouzi, Imed. / The cleavage of HuR interferes with its transportin-2-mediated nuclear import and promotes muscle fiber formation. In: Cell Death and Differentiation. 2010 ; Vol. 17, No. 10. pp. 1588-1599.
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