View the Current Issue

Article

  • The EMBO Journal advance online publication 22 October 2009; doi:10.1038/emboj.2009.296

Calreticulin-dependent recycling in the early secretory pathway mediates optimal peptide loading of MHC class I molecules

Christopher Howe1,4, Malgorzata Garstka2,54, Mohammed Al-Balushi2,3, Esther Ghanem2, Antony N Antoniou1,6, Susanne Fritzsche2, Gytis Jankevicius2, Nasia Kontouli1, Clemens Schneeweiss2, Anthony Williams1, Tim Elliott1,7 and Sebastian Springer2,7

  1. Cancer Sciences Division, University of Southampton School of Medicine, Southampton, UK
  2. Department of Biochemistry and Cell Biology, Jacobs University, Bremen, Germany
  3. Department of Microbiology and Immunology, Sultan Qaboos University, Muscat, Oman

Correspondence to:

Sebastian Springer, Biochemistry and Cell Biology, School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany. Tel.: +49 421 200 3243; Fax: +49 421 200 3249; E-mail: s.springer@jacobs-university.de

Tim Elliott, Cancer Sciences Division, Somers Cancer Research Building, University of Southampton School of Medicine, Mailpoint 824, Southampton General Hospital, Southampton SO16 6YD, UK. Tel.: +44 2380 796193; Fax: +44 2380 795152; E-mail: T.J.Elliott@soton.ac.uk

4Present address: Division of Tumor Biology, The Netherlands Cancer Institute, P.O. Box 90203, 1066BE Amsterdam, The Netherlands

5Present address: Department of Immunology & Molecular Pathology, Windeyer Institute of Medical Science, University College London, London W1P 6DB, UK

6These authors contributed equally to this work

7Joint senior authors.

Received 19 March 2009; Accepted 14 September 2009

Calreticulin is a lectin chaperone of the endoplasmic reticulum (ER). In calreticulin-deficient cells, major histocompatibility complex (MHC) class I molecules travel to the cell surface in association with a sub-optimal peptide load. Here, we show that calreticulin exits the ER to accumulate in the ER–Golgi intermediate compartment (ERGIC) and the cis-Golgi, together with sub-optimally loaded class I molecules. Calreticulin that lacks its C-terminal KDEL retrieval sequence assembles with the peptide-loading complex but neither retrieves sub-optimally loaded class I molecules from the cis-Golgi to the ER, nor supports optimal peptide loading. Our study, to the best of our knowledge, demonstrates for the first time a functional role of intracellular transport in the optimal loading of MHC class I molecules with antigenic peptide.

  • Keywords:

    • calreticulin,
    • endoplasmic reticulum,
    • major histocompatibility complex (MHC) class I molecules,
    • peptides,
    • quality control