Thursday, 14th December 2017
Cell Biology and Immunology
             Mechanism of association of HLA-B27 with spondyloarthropathies

 

 
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José Antonio López de Castro

ASciStaff

APublications

 

Research summary:

The pathogenetic role of HLA-B27 in ankylosing spondylitis (AS) is among the most challenging issues in MHC immunopathology. The HLA-B27 peptidome is crucial, as it determines the immunological features of HLA-B27, its folding and stability. This concept is strongly supported by the association of ERAP1, an aminopeptidase of the endoplasmic reticulum that trims peptides to their optimal length for MHC-I binding, with AS. In the last two years our laboratory focused on the role of the proteasome and ERAP1 in shaping the peptidomes of HLA-B27 and a second MHC-I molecule, HLA-A68, that shares with HLA-B27 some peptide binding features, using comparative mass spectrometry. The proteasome-inhibitor-resistant HLA-A68 peptidome revealed that proteasome inhibitors fail to achieve total inhibition, substantially altering proteasomal cleavage patterns. Yet, these alterations did not increase the expression of MHC-I epitopes that might be destroyed by an intact proteasome. Rather, it appears that, upon incomplete proteasomal inhibition, post-proteasomal processing results in a substantial generation of inhibitor-resistant MHC-I ligands from incompletely degraded proteins. Concerning ERAP1, we demonstrated, for the first time in vivo, that natural ERAP1 variants have an extensive influence on the HLA-B27 peptidome. The mechanism of functional ERAP1/HLA-B27 interaction in AS is an allotype-dependent alteration in the balance between epitope generation and destruction. ERAP1 polymorphism associated with AS susceptibility ensured efficient peptide trimming and high HLA-B27 stability. Protective polymorphism resulted in diminished ERAP1 activity, suboptimal HLA-B27 peptidomes and decreased molecular stability.

fig01-300 

Localization of natural AS-associated polymorphism in the three-dimensional structure of ERAP1. Polymorphic residues are located in areas that potentially influence substrate binding or catalytic activity.

 

PATHWAYS REGULATING PROTEOSTASIS IN TUMOR CELLS (LCA). Using specific activity probes we have identified some pathways crucial for the survival of tumor cell lines, allowing their adaptation to their constitutive proteotoxic stress. We also identified potential targets that would allow the manipulation of this adaptation, in particular members of the ubicuitin-hydrolase family.


 

Relevant publications:

  • García-Medel, N., Sanz, A., Barnea, E., Admon, A., and Jose A. López de Castro, J.A. (2012). The origin of proteasome-inhibitor resistant HLA class I peptidomes: a study with HLA-A*68:01. Mol. Cell. Proteomics 11: 1-15.doi: 10.1074/mcp.M111.011486. PM:21969608.
  • García-Medel, N., Sanz-Bravo, A., Van Nguyen, D., Galocha, B., Gómez-Molina, P., Martín-Esteban, A., Alvarez-Navarro, C., and López de Castro, J.A. (2012) Functional Interaction of the Ankylosing Spondylitis Associated Endoplasmic Reticulum Aminopeptidase 1 Polymorphism and HLA-B27 in vivo. Mol. Cell. Proteomics. 11: 1416-1429. doi:10.1074/mcp.M112.019588. PM:22918227.

 

Doctoral theses:

Noel García-Medel (2012). Contribución del proteasoma y del polimorfismo de ERAP1en la configuración y patogenicidad de los peptidomas constitutivos de MHC-I: Estudios en HLA-A68 y HLA-B27. Universidad Autónoma de Madrid. Director: José A. López de Castro.