Tumor-associated calreticulin variants functionally compromise the peptide loading complex and impair its recruitment of MHC-I.

The Journal of Biological Chemistry
Najla Arshad, P Cresswell

Abstract

Major histocompatibility complex-I-β2m dimers (MHC-I) bind peptides derived from intracellular proteins, enabling the immune system to distinguish between normal cells and those expressing pathogen-derived or mutant proteins. The peptides bind to MHC-I in the endoplasmic reticulum (ER), and this binding is facilitated by the peptide loading complex (PLC), which contains calreticulin (CRT). CRT associates with MHC-I via a conserved glycan present on MHC-I and recruits it to the PLC for peptide binding. Somatic frameshift mutations in CRT (CRT-FS) drive the proliferation of a subset of myeloproliferative neoplasms, which are chronic blood tumors. All CRT-FS proteins have a C-terminal sequence lacking the normal ER-retention signal and possessing a net negative charge rather than the normal positive charge. We characterized the effect of CRT-FS on antigen presentation by MHC-I in human cells. Our results indicate that CRT-FS cannot mediate CRT's peptide loading function in the PLC. Cells lacking CRT exhibited reduced surface MHC-I levels, consistent with reduced binding of high-affinity peptides, and this was not reversed by CRT-FS expression. CRT-FS was secreted and not detectably associated with the PLC, leading to poor MHC-I re...Continue Reading

References

Sep 1, 1978·British Medical Bulletin·C J BarnstableM J Crumpton
Mar 23, 2001·Nature Immunology·N GarbiG J Hämmerling
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Apr 19, 2006·The Journal of Biological Chemistry·Arik Cooper, Yosef Shaul
Jun 3, 2006·Developmental Cell·Eric MaciaTomas Kirchhausen
Dec 26, 2006·Nature Medicine·Michel ObeidGuido Kroemer
Nov 21, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Maya W Everett, Michael Edidin
Apr 14, 2009·Nature Methods·Daniel G GibsonHamilton O Smith
Feb 19, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Ralf M LeonhardtMichael R Knittler
Nov 11, 2010·Current Cancer Drug Targets·Susanne HofmannJochen Greiner
Mar 9, 2011·Proceedings of the National Academy of Sciences of the United States of America·Pamela A WearschPeter Cresswell
Jun 10, 2011·The Journal of Biological Chemistry·Cosmin L PocanschiKalle Gehring
Jul 26, 2012·The Journal of Biological Chemistry·Michaela S PanterPeter Cresswell
Jan 10, 2013·Annual Review of Immunology·Janice S BlumPeter Cresswell
Apr 19, 2013·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jennifer C ByrneCaroline A Jefferies
Jul 16, 2013·Journal of the National Cancer Institute·Patrizia LeoneVito Racanelli
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang
Dec 12, 2013·The New England Journal of Medicine·Thorsten KlampflRobert Kralovics
Dec 12, 2013·The New England Journal of Medicine·J NangaliaA R Green
Dec 17, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Gregory L Beatty, Whitney L Gladney
Nov 6, 2015·Mediators of Inflammation·Sylvie HermouetBetty Gardie
Nov 18, 2015·American Journal of Hematology·Michael R GarbatiKim-Hien T Dao

❮ Previous
Next ❯

Citations

Jan 30, 2019·Immunogenetics·Peter Cresswell
Feb 1, 2020·Annual Review of Biophysics·Simon Trowitzsch, Robert Tampé
Jan 23, 2019·Frontiers in Immunology·Sebastian Montealegre, Peter M van Endert
Jan 28, 2020·The Journal of Clinical Investigation·Livius Penter, Catherine J Wu
Oct 6, 2020·F1000Research·Anita J ZaitouaMalini Raghavan
Dec 19, 2019·International Journal of Hematology·Marito Araki, Norio Komatsu
Sep 29, 2019·Blood·Joan HowAnn Mullally
Aug 1, 2020·Cell Research·Jitka FucikovaLorenzo Galluzzi
Dec 24, 2018·Journal of Biotechnology·Barbara ZiffelsDario Neri
Dec 2, 2019·Molecular Cell·Peng LiuGuido Kroemer
Mar 4, 2021·Cancers·Ana Guijarro-Hernández, José Luis Vizmanos
Mar 23, 2021·Nature Reviews. Cancer·Suchit JhunjhunwalaLélia Delamarre
Apr 29, 2021·The Journal of Cell Biology·Arunkumar VenkatesanMalini Raghavan
Jun 4, 2021·Molecular Immunology·M L M JongsmaR M Spaapen
Jun 8, 2021·HemaSphere·Stefan N ConstantinescuNicolas Papadopoulos
Aug 7, 2021·Biochimica Et Biophysica Acta. Proteins and Proteomics·Evaldas ČiplysRimantas Slibinskas
Aug 28, 2021·Journal of Cellular and Molecular Medicine·Anita RoySaadia Naseer

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.