N-TERMINAL POST-TRANSLATIONAL ARGINYLATION REGULATES MULTIPLE ROLES OF CALRETICULIN

GALIANO MR; BONNET LV; ANDREA COMBA; GOITEA, VICTOR E.; CARPIO M; HALLAK ME

Paraná

Congreso; Sociedad Argentina de Investigación Bioquímica y Biología Molecular; 2018

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

In cell, post-translational arginylation of proteins regulates many physiological pathways. The enzyme arginyltransferase (Ate1) catalyzes Arg transfer to proteins and polypeptides bearing an N-terminal Glu or Asp residues. Among different substrates, this modification facilitates ubiquitin-ligase recognition and degradation, protein-protein interaction or change of subcellular distribution of protein targets. In our research we identified calreticulin (CRT) as one Ate1 substrate. Different stressors induce retrotranslocation of this endoplasmic reticulum (ER)-chaperone to the cytosol, where CRT is modified by Ate1. Once modified, arginylated CRT (R-CRT) may associate with stress granules (SGs) or localize to the plasma membrane, participating of pro-apoptotic signals. Recently, we reported a correlation between R-CRT localization and the sensitivity to the proteasomal inhibitor bortezomib of glioma-derived cells. This drug induces enhanced mobilization of intracellular Ca2+ and ER stress, promoting increased arginylation of CRT and membrane exposure of R-CRT in bortezomib sensitive cells. Upregulation of cell death receptor DR5 is also associated with the R-CRT-mediated apoptosis mechanism induced by bortezomib. Our results suggest that increased R-CRT membrane exposure provides a novel mechanism to improve bortezomib effectiveness for glioma treatment and support Ate1 as a target for cancer therapy.