Endoplasmic reticulum chaperones stabilize ligand-receptive MR1 molecules for efficient presentation of metabolite antigens.
Proc Natl Acad Sci U S A
; 117(40): 24974-24985, 2020 10 06.
Article
in En
| MEDLINE
| ID: mdl-32958637
ABSTRACT
The antigen-presenting molecule MR1 (MHC class I-related protein 1) presents metabolite antigens derived from microbial vitamin B2 synthesis to activate mucosal-associated invariant T (MAIT) cells. Key aspects of this evolutionarily conserved pathway remain uncharacterized, including where MR1 acquires ligands and what accessory proteins assist ligand binding. We answer these questions by using a fluorophore-labeled stable MR1 antigen analog, a conformation-specific MR1 mAb, proteomic analysis, and a genome-wide CRISPR/Cas9 library screen. We show that the endoplasmic reticulum (ER) contains a pool of two unliganded MR1 conformers stabilized via interactions with chaperones tapasin and tapasin-related protein. This pool is the primary source of MR1 molecules for the presentation of exogenous metabolite antigens to MAIT cells. Deletion of these chaperones reduces the ER-resident MR1 pool and hampers antigen presentation and MAIT cell activation. The MR1 antigen-presentation pathway thus co-opts ER chaperones to fulfill its unique ability to present exogenous metabolite antigens captured within the ER.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Histocompatibility Antigens Class I
/
Minor Histocompatibility Antigens
/
Proteomics
/
Endoplasmic Reticulum
/
Metabolome
Limits:
Humans
Language:
En
Journal:
Proc Natl Acad Sci U S A
Year:
2020
Type:
Article