I-Ag7 is subject to post-translational chaperoning by CLIP.
Several MHC class II alleles linked with autoimmune diseases form unusually low-stability complexes with class II-associated invariant chain peptides (CLIP), leading us to hypothesize that this is an important feature contributing to autoimmune pathogenesis. We recently demonstrated a novel post-endoplasmic reticulum (ER) chaperoning role of the CLIP peptides for the murine class II allele I-E(d). In the current study, we tested the generality of this CLIP chaperone function using a series of invariant chain (Ii) mutants designed to have varying CLIP affinity for I-A(g7). In cells expressing these Ii CLIP mutants, I-A(g7) abundance, turnover and antigen presentation are all subject to regulation by CLIP affinity, similar to I-E(d). However, I-A(g7) undergoes much greater quantitative changes than observed for I-E(d). In addition, we find that Ii with a CLIP region optimized for I-A(g7) binding may be preferentially assembled with I-A(g7) even in the presence of higher levels of wild-type Ii. This finding indicates that, although other regions of Ii interact with class II, CLIP binding to the groove is likely to be a dominant event in assembly of nascent class II molecules with Ii in the ER.
Rinderknecht
Cornelia H
CH
Program in Immunology, Stanford University, Stanford, CA 94305, USA.
Lu
Ning
N
Crespo
Oliver
O
Truong
Phi
P
Hou
Tieying
T
Wang
Nan
N
Rajasekaran
Narendiran
N
Mellins
Elizabeth D
ED
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D015151:Immunoblotting; D051379:Mice; D008807:Mice, Inbred BALB C; D018832:Molecular Chaperones / Q000276:immunology*; D009154:Mutation; D011499:Protein Processing, Post-Translational / Q000276:immunology*
D000944:Antigens, Differentiation, B-Lymphocyte; D000954:Antigens, Surface; D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D018832:Molecular Chaperones; C045084:invariant chain