The structure and location of SIMP/STT3B account for its prominent imprint on the MHC I immunopeptidome

Abstract

Proteins show drastic discrepancies in their contribution to the collection of self-peptides that shape the repertoire of CD8 T cells (MHC I self-immunopeptidome). To decipher why selected proteins are the foremost sources of MHC I-associated self-peptides, we chose to study SIMP/STT3B because this protein generates very high amounts of MHC I-associated peptides in mice and humans. We show that the endoplasmic reticulum (ER)-associated degradation pathway and MHC I processing intersect at SIMP/STT3B. Relevant key features of SIMP/STT3B are its lysine-rich region, its propensity to misfold and its location in the ER membrane in close proximity to the immunoproteasome. Moreover, we show that coupling to SIMP/STT3B can be used to foster MHC I presentation of a selected peptide, here the ovalbumin peptide SIINFEKL. These data yield novel insights into relations between the cell proteome and the MHC I immunopeptidome. They suggest that the contribution of a given protein to the MHC I immunopeptidome results from the interplay of at least three factors: the presence of degrons (degradation signals), the tendency of the protein to misfold and its subcellular localization. Furthermore, they indicate that substrates of the ER-associated degradation pathway may have a prominent imprint on the MHC I self-immunopeptidome.

Analysis of Major Histocompatibility Complex (MHC) Immunopeptidomes Using Mass Spectrometry*

“…We also highlight selected biological applications and discuss important current technical limitations that need to be solved to accelerate the development of this field. The immunopeptidome is referred to as the collection of peptides associated with and presented by major histocompatibility complex (MHC) molecules (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). MHC-associated peptides are recognized by T lymphocytes that are in turn activated to eliminate abnormal cells such as pathogen-infected and cancer cells.…”

Cloning, characterization and expression analysis of SIMP (source of immunodominant MHC-associated peptides) in grass carp Ctenopharyngodon idella

“…2) is based on SOSUI and TOPO2 (http://www.sacs.ucsf. edu/TOPO2/) prediction methods [20]. Multiple alignments were generated at the web site (http://searchlauncher.…”

“…In addition to the role in N-linked glycosylation, SIMP also plays roles in the MHC I presentation pathway by being the source of MHC-peptides and displaying a small number of immunopeptidomes for recognition by CD8T cells [14e16], which is not for TMC [10,17e19]. Recently, N-glycosylation sites in SIMP were found to make a contribution to SIMP retrotranslocation and degradation, which is one source of MHC I-presented peptides [20,21]. The unique characteristic of SIMP highlights its potential importance in protein modification and immune therapy.…”

“…The function of SIMP has been preliminarily studied recently [20,21]. SIMP has first been characterized in grass carp Ctenopharyngodon idella by utilizing suppression subtractive hybridization (SSH) in a previous study [22].…”

Immunothérapie anti-cancer sans dommages collatéraux

“…Tout d'abord, il est très immunogène et est abondamment exprimé à la surface cellulaire. Ensuite, il provient d'une protéine (STT3B) dont les cellules néopla-siques ne peuvent réprimer l'expression [8,9]. Ces paramètres devront être pris en considération lors de l'élaboration de stratégies transposables à l'humain.…”