Directed inhibition of nuclear import in cellular hypertrophy.
Each nuclear pore is responsible for both nuclear import and export with a finite capacity for bidirectional transport across the nuclear envelope. It remains poorly understood how the nuclear transport pathway responds to increased demands for nucleocytoplasmic communication. A case in point is cellular hypertrophy in which increased amounts of genetic material need to be transported from the nucleus to the cytosol. Here, we report an adaptive down-regulation of nuclear import supporting such an increased demand for nuclear export. The induction of cardiac cell hypertrophy by phenylephrine or angiotensin II inhibited the nuclear translocation of H1 histones. The removal of hypertrophic stimuli reversed the hypertrophic phenotype and restored nuclear import. Moreover, the inhibition of nuclear export by leptomycin B rescued import. Hypertrophic reprogramming increased the intracellular GTP/GDP ratio and promoted the nuclear redistribution of the GTP-binding transport factor Ran, favoring export over import. Further, in hypertrophy, the reduced creatine kinase and adenylate kinase activities limited energy delivery to the nuclear pore. The reduction of activities was associated with the closure of the cytoplasmic phase of the nuclear pore preventing import at the translocation step. Thus, to overcome the limited capacity for nucleocytoplasmic transport, cells requiring increased nuclear export regulate the nuclear transport pathway by undergoing a metabolic and structural restriction of nuclear import.
Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905, USA. terzic.andre@mayo.edu
C
C
Perez-Terzic
A M
AM
Gacy
R
R
Bortolon
P P
PP
Dzeja
M
M
Puceat
M
M
Jaconi
F G
FG
Prendergast
A
A
Terzic
D000818:Animals; D001692:Biological Transport; D002467:Cell Nucleus / Q000378:metabolism*; D048429:Cell Size; D015536:Down-Regulation; D009711:Nucleotides / Q000378:metabolism*; D010641:Phenotype; D051381:Rats
D009711:Nucleotides