N-terminal post-translational arginylation regulates multiple roles of calreticulin

GALIANO, MAURICIO R.; BONNET, LAURA V.; ANDREA COMBA; GOITEA, VICTOR E.; MARCOS A. CARPIO; HALLAK, MARTA E.

Paraná, Entre Ríos

Congreso; Congreso SAIB 2018; 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 Argtransfer to proteins and polypeptides bearing an N-terminal Glu or Asp residues. Among different substrates, this modification facilitatesubiquitin-ligase recognition and degradation, protein-protein interaction or change of subcellular distribution of protein targets. In our researchwe 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 andthe 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 celldeath receptor DR5 is also associated with the R-CRT-mediated apoptosis mechanism induced by bortezomib. Our results suggest that increasedR-CRT membrane exposure provides a novel mechanism to improve bortezomib effectiveness for glioma treatment and support Ate1 as a targetfor cancer therapy.