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

Christopher Howe1, Malgorzata Garstka, Mohammed Al-Balushi

  • 1Cancer Sciences Division, University of Southampton School of Medicine, Southampton, UK.

The EMBO Journal
|October 24, 2009
PubMed

Insights

Calreticulin

Area of Science:

  • Immunology
  • Cell Biology
  • Molecular Biology

Background:

  • Calreticulin functions as an endoplasmic reticulum (ER) lectin chaperone.
  • In calreticulin-deficient cells, Major Histocompatibility Complex (MHC) class I molecules exhibit suboptimal peptide loading.
  • MHC class I molecules are crucial for presenting antigenic peptides to T cells.

Purpose of the Study:

  • To investigate the role of calreticulin's intracellular transport in Major Histocompatibility Complex (MHC) class I peptide loading.
  • To determine if calreticulin's localization within the secretory pathway influences MHC class I loading.
  • To elucidate the functional consequences of calreticulin's interaction with the peptide-loading complex.

Main Methods:

  • Immunofluorescence microscopy to track calreticulin and MHC class I localization.
  • Biochemical assays to assess peptide loading efficiency.
  • Analysis of cells expressing wild-type and mutant calreticulin (lacking KDEL sequence).

Main Results:

  • Calreticulin relocates from the ER to the ER-Golgi intermediate compartment (ERGIC) and cis-Golgi, co-localizing with inadequately peptide-loaded MHC class I molecules.
  • Calreticulin lacking its C-terminal KDEL retrieval sequence can associate with the peptide-loading complex.
  • This KDEL-deficient calreticulin fails to retrieve MHC class I from the cis-Golgi to the ER and does not enhance peptide loading.

Conclusions:

  • Intracellular transport of calreticulin plays a critical role in achieving optimal peptide loading of MHC class I molecules.
  • Calreticulin's localization within specific compartments of the secretory pathway is essential for its function in MHC class I peptide loading.
  • The C-terminal KDEL sequence is vital for calreticulin's retrieval function and subsequent support of optimal MHC class I peptide loading.

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