Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in {beta}-cells.
Islet cell autoantigen 512 (ICA512)/IA-2 is a receptor tyrosine phosphatase-like protein associated with the insulin secretory granules (SGs) of pancreatic beta-cells. Here, we show that exocytosis of SGs and insertion of ICA512 in the plasma membrane promotes the Ca(2+)-dependent cleavage of ICA512 cytoplasmic domain by mu-calpain. This cleavage occurs at the plasma membrane and generates an ICA512 cytosolic fragment that is targeted to the nucleus, where it binds the E3-SUMO ligase protein inhibitor of activated signal transducer and activator of transcription-y (PIASy) and up-regulates insulin expression. Accordingly, this novel pathway directly links regulated exocytosis of SGs and control of gene expression in beta-cells, whose impaired insulin production and secretion causes diabetes.
Trajkovski
Mirko
M
Experimental Diabetology, Carl Gustav Carus Medical School, Dresden University of Technology, Dresden, Germany.
Mziaut
Hassan
H
Altkrüger
Anke
A
Ouwendijk
Joke
J
Knoch
Klaus-Peter
KP
Müller
Stefan
S
Solimena
Michele
M
D000818:Animals; D001324:Autoantigens / Q000378:metabolism*; D002154:Calpain / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology*; D005260:Female; D006801:Humans; D007328:Insulin / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8
D001324:Autoantigens; D007328:Insulin; D008565:Membrane Proteins; D010446:Peptide Fragments; C516862:PTPRN protein, human; D017027:Protein Tyrosine Phosphatases; C516864:Ptprn protein, rat; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D002154:Calpain; C449002:mu-calpain