Arginylated Calreticulin at Plasma Membrane Increases Susceptibility of Cells to Apoptosis

• Published in: The Journal of biological chemistry Vol. 287; no. 26; pp. 22043 - 22054
• Main Authors: López Sambrooks, Cecilia, Carpio, Marcos A., Hallak, Marta E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22-06-2012; American Society for Biochemistry and Molecular Biology
• Subjects: Aminoacyltransferases - metabolism; Animals; Apoptosis; Arginine - chemistry; Arginine - metabolism; Arginylation; Biotinylation; Calcium - metabolism; Calcium Signaling; Calreticulin; Calreticulin - chemistry; Cell Biology; Cell Membrane - metabolism; Cell Surface Protein; Endoplasmic Reticulum - metabolism; Fibroblasts - cytology; Flow Cytometry - methods; Mice; Mice, Transgenic; Post-translational Modifications; Protein Processing, Post-Translational; Streptavidin - metabolism; Stress Granule; Stress Response; Calreticulin; Post-translational Modifications; Cell Surface Protein; Stress Granule; Stress Response; Arginylation; Calcium Signaling; Apoptosis
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.338335

Post-translational modifications of proteins are important for the regulation of cell fate and functions; one of these post-translational modifications is arginylation. We have previously established that calreticulin (CRT), an endoplasmic reticulum resident, is also one of the arginylated substrates found in the cytoplasm. In the present study, we describe that arginylated CRT (R-CRT) binds to the cell membrane and identified its role as a preapoptotic signal. We also show that cells lacking arginyl-tRNA protein transferase are less susceptible to apoptosis than wild type cells. Under these conditions R-CRT is present on the cell membrane but at early stages is differently localized in stress granules. Moreover, cells induced to undergo apoptosis by arsenite show increased R-CRT on their cell surface. Exogenously applied R-CRT binds to the cell membrane and is able to both increase the number of cells undergoing apoptosis in wild type cells and overcome apoptosis resistance in cells lacking arginyl-tRNA protein transferase that express R-CRT on the cell surface. Thus, these results demonstrate the importance of surface R-CRT in the apoptotic response of cells, implying that post-translational arginylation of CRT can regulate its intracellular localization, cell function, and survival.
Calreticulin retrotranslocated from the endoplasmic reticulum to the cytoplasm is post-translationally arginylated associates to stress granules following stress that decrease Ca2+.
Arginylated calreticulin reaches the plasma membrane as a response to stress.
Arginylation confers to calreticulin a function as one of the preapoptotic signals of the cells.
Arginylated calreticulin is a novel factor involved in stress-induced apoptosis.