Cabecera 2019 CBMSO CSIC UAM

Thursday, 17th October 2019

Metabolic homeostasis

 

Grup ISandoval 400
 


Ignacio Vicente Sandoval

ASciStaff

APublications

 

Research summary:

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Cu+- induced relocation of the Cu+ transporter ATP7B from the trans-Golgi network to the bile canaliculus in CAN 10 hepatoma cells. Cells treated with Cu+ as indicated in the panels were studied for ATP7B location. Note the early transit of ATP7B through the cell basolateral domain (area delineated by the white dotted lines and the far end of the β catenin labelled plasma membrane) and the localization of ATP7B in the bile canaliculi, sealed by the ZO-1 positive tight junctions, after extensive treatment with Cu+.

 

 

 

 

 

 

 

 

 

 

 

The transition metal copper (Cu+) is an essential trace element for all biota. Its redox properties bestow Cu with capabilities that are simultaneously essential and potentially damaging to the cell. Free Cu is virtually absent in the cell. In mammalians liver is the major captor, distributor and excreter of Cu. Humans eliminate 95% of the Cu+ ingested with diet. The excretion of Cu into the bile is an attribute exclusive of the hepatocyte and bile is the major route of Cu elimination and the most important mechanism in Cu homoeostasis in mammals. The correlation between the release of ATP7B retained in the trans-Golgi network (TGN) and the role of ATP7B in excretion of Cu into the bile is firmly established. Yet, the pathway of ATP7B transport is poorly understood and its site of action is the subject of a hot debate. Our studies of Cu+-mediated ATP7B traffic in CAN 10 hepatoma cells showed that after its release from the TGN, ATP7B is basolateral sorted, inserted in the basolateral plasma membrane and transported by transcytosis to the bile canaliculus (BC). Insertion of ATP7B into the membrane of the BC is essential for excreting excess of cellular Cu+ into the medium. Contradicting recent reports, our studies find no evidence of ATP7B association with lysosomes and do not support the recent model of Cu+ excretion mediated by lysosome exocytosis. In recent months we have started a systematic study of the mutations that disrupt ATP7B traffic and cause Wilson disease and cuprotoxicosis with a genetic background of wild ATP7B. In a separate study we investigate the role of ESyt proteins in membrane dynamics and glucose and lipid metabolism in the adipocyte. New inroads in understanding the functioning of Esyt3, a protein associated with the endoplasmic reticulum (ER) that is believed to play a key role in anchoring the ER to the plasma membrane, include: the mapping of the Ca++ and phospholipid binding to the BM y C2-1,C2-2 y C2-3 domains; the characterization of its physical interaction with gelsolin; its role in lipid droplet biogenesis. Finally the study of the toroidal structure produced by polymerization of IMPDH2 is in progress and the study of the HDAC enhancer C6orf89 has been completed.


 

Relevant publications:

  • DKWSLLL, a versatile DXXXLL-type signal with distinct roles in the Cu(+)-regulated trafficking of ATP7B.Lalioti V, Hernandez-Tiedra S, Sandoval IV.Traffic. 2014 Aug;15(8):839-60. 2014 Jun 24.
  • Sorcin links calcium signaling to vesicle trafficking, regulates Polo-like kinase 1 and is necessary for mitosis. Lalioti VS, Ilari A, O'Connell DJ, Poser E, Sandoval IV, Colotti G.PLoS One. 2014 Jan 10;
  • Molecular mechanism and functional role of brefeldin A-mediated ADP-ribosylation of CtBP1/BARS. Colanzi A, Grimaldi G, Catara G, Valente C, Cericola C, Liberali P, Ronci M, Lalioti VS, Bruno A, Beccari AR, Urbani A, De Flora A, Nardini M, Bolognesi M, Luini A, Corda D. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9794-9. doi: 10.1073/pnas.1222413110. Epub 2013 May 28.
  • C6orf89 encodes three distinct HDAC enhancers that function in the nucleolus, the golgi and the midbody. Lalioti VS, Vergarajauregui S, Villasante A, Pulido D, Sandoval IV.J Cell Physiol. 2013 Sep;228(9):1907-21.

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