title: The nucleoporin gp210/Nup210 controls muscle differentiation by regulating nuclear envelope/ER homeostasis.
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.
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037 Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093.
authors.forename: J Sebastian
authors.initials: JS
authors.lastname: Gomez-Cavazos
authors.affiliation: Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037 hetzer@salk.edu.
authors.forename: Martin W
authors.initials: MW
authors.lastname: Hetzer
mesh_terms: D000818:Animals; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D006706:Homeostasis; D006801:Humans; D051379:Mice; D024510:Muscle Development; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009685:Nuclear Envelope; D028861:Nuclear Pore Complex Proteins / Q000502:physiology*; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats
chemical_list: D028861:Nuclear Pore Complex Proteins; C512902:Nup210 protein, mouse; D020169:Caspases