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Tumor-associated calreticulin variants functionally compromise the peptide loading complex and impair its recruitment of MHC-I
- Publication Year :
- 2018
- Publisher :
- American Society for Biochemistry and Molecular Biology, 2018.
-
Abstract
- Major histocompatibility complex-I–β(2)m 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 recruitment, although CRT-FS could still associate with MHC-I in a glycan-dependent manner. The addition of an ER-retention sequence to CRT-FS restored its association with the PLC but did not rescue MHC-I recruitment or its surface expression, indicating that the CRT-FS mutants functionally compromise the PLC. MHC-I down-regulation permits tumor cells to evade immune surveillance, and these findings may therefore be relevant for designing effective immunotherapies for managing myeloproliferative neoplasms.
- Subjects :
- 0301 basic medicine
genetic structures
Antigen presentation
Immunology
Peptide binding
Major histocompatibility complex
Biochemistry
03 medical and health sciences
Neoplasms
MHC class I
Humans
cardiovascular diseases
Molecular Biology
Antigen Presentation
biology
Antigen processing
Chemistry
Endoplasmic reticulum
Histocompatibility Antigens Class I
Cell Biology
equipment and supplies
Peptide Fragments
Cell biology
030104 developmental biology
Secretory protein
HEK293 Cells
Mutation
biology.protein
cardiovascular system
Calreticulin
circulatory and respiratory physiology
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....7f32d39b807365f8812b28969129ba73