The nucleoporin gp210/Nup210 controls muscle differentiation by regulating nuclear envelope/ER homeostasis

J Cell Biol. 2015 Mar 16;208(6):671-81. doi: 10.1083/jcb.201410047.

Abstract

Previously, we identified the nucleoporin gp210/Nup210 as a critical regulator of muscle and neuronal differentiation, but how this nucleoporin exerts its function and whether it modulates nuclear pore complex (NPC) activity remain unknown. Here, we show that gp210/Nup210 mediates muscle cell differentiation in vitro via its conserved N-terminal domain that extends into the perinuclear space. Removal of the C-terminal domain, which partially mislocalizes gp210/Nup210 away from NPCs, efficiently rescues the differentiation defect caused by the knockdown of endogenous gp210/Nup210. Unexpectedly, a gp210/Nup210 mutant lacking the NPC-targeting transmembrane and C-terminal domains is sufficient for C2C12 myoblast differentiation. We demonstrate that the endoplasmic reticulum (ER) stress-specific caspase cascade is exacerbated during Nup210 depletion and that blocking ER stress-mediated apoptosis rescues differentiation of Nup210-deficient cells. Our results suggest that the role of gp210/Nup210 in cell differentiation is mediated by its large luminal domain, which can act independently of NPC association and appears to play a pivotal role in the maintenance of nuclear envelope/ER homeostasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caspases / metabolism
  • Cell Differentiation*
  • Cell Line
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Stress
  • Homeostasis*
  • Humans
  • Mice
  • Muscle Development
  • Muscle Fibers, Skeletal / physiology
  • Nuclear Envelope
  • Nuclear Pore Complex Proteins / physiology*
  • Protein Structure, Tertiary
  • Protein Transport
  • Rats

Substances

  • Nuclear Pore Complex Proteins
  • Nup210 protein, mouse
  • Caspases