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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.00411

Integrins and ERp57 coordinate to regulate cell surface calreticulin in immunogenic cell death.

Chi-Chao Liu1, Pascal Leclair1, Foujan Pedari1, Heidi Vieira1, Mahdis Monajemi1,  Laura M. Sly1, Gregor S. Reid1 and  Chinten J. Lim1, 2*
  • 1University of British Columbia, Canada
  • 2Pediatrics, University of British Columbia, Canada

Therapy-induced presentation of cell surface calreticulin (CRT) is a pro-phagocytic immunogen beneficial for invoking anti-tumour immunity. Here, we characterized the roles of ERp57 and α-integrins as CRT-interacting proteins that coordinately regulate CRT translocation from the ER to the surface during immunogenic cell death. Using T-lymphoblasts as a genetic cell model, we found that drug-induced surface CRT is dependent on ERp57, while drug-induced surface ERp57 is independent of CRT. Differential subcellular immunostaining assays revealed that ERp57-/- cells have minimal cytosolic CRT, indicating that ERp57 is indispensable for extra-ER accumulation of CRT. Stimulation of integrin activity, with either cell adhesion or molecular agonists, resulted in decreased drug-induced surface CRT and ERp57 levels. Similarly, surface CRT and ERp57 was reduced in cells expressing GFFKR, a conserved α-integrin cytosolic motif that binds CRT. Drug-induced surface ERp57 levels were consistently higher in CRT-/- cells, suggesting integrin inhibition of surface ERp57 is an indirect consequence of α-integrin binding to CRT within the CRT-ERp57 complex. Furthermore, β1-/- cells with reduced expression of multiple α-integrins, exhibit enhanced levels of drug-induced surface CRT and ERp57. Our findings highlight the coordinate involvement of plasma membrane integrins as inhibitors, and ERp57 originating from the ER as promoters, of CRT translocation from the ER to cell surface.

Keywords: Integrins, Immunogenic cell death (ICD), ERp57 (endoplasmic reticulum protein 57), Calreticulin, Acute lymhoblastic leukaemia

Received: 07 Feb 2019; Accepted: 02 May 2019.

Edited by:

Juan J. Lasarte, Center of Applied Medical Research, School of Pharmacy and Nutrition, University of Navarra, Spain

Reviewed by:

Oliver Kepp, Institut Gustave Roussy, France
Jonathan Pol, Institut National de la Santé et de la Recherche Médicale (INSERM), France
Ken Maes, Vrije University Brussel, Belgium  

Copyright: © 2019 Liu, Leclair, Pedari, Vieira, Monajemi, Sly, Reid and Lim. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Chinten J. Lim, University of British Columbia, Pediatrics, Vancouver, V5Z4H4, British Columbia, Canada, cjlim@mail.ubc.ca