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J. Biol. Chem., Vol. 277, Issue 48, 46478-46486, November 29, 2002
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From the A common T17A polymorphism in the signal
peptide of the cytotoxic T-lymphocyte antigen 4 (CTLA-4), a T-cell
receptor that negatively regulates immune responses, is associated with
risk for autoimmune disease. Because the polymorphism is absent from the mature protein, we hypothesized that its biological effect must
involve early stages of protein processing, prior to signal peptide
cleavage. Constructs representing the two alleles were compared by
in vitro translation, in the presence of endoplasmic reticulum membranes. We studied glycosylation by endoglycosidase H digestion and glycosylation mutant constructs, cleavage of peptide with inhibitors, and membrane integration by ultracentrifugation and
proteinase K sensitivity. A major cleaved and glycosylated product was
seen for both alleles of the protein but a band representing incomplete
glycosylation was markedly more abundant in the predisposing Ala allele
(32.7 ± 1.0 versus 10.6% ± 1.2 for Thr,
p < 10
A Common Autoimmunity Predisposing Signal Peptide Variant of the
Cytotoxic T-lymphocyte Antigen 4 Results in Inefficient Glycosylation
of the Susceptibility Allele*
§,,, and
Endocrine Genetics Laboratory, Department of
Pediatrics, Division of Pediatric Endocrinology, McGill University
Health Center, 2300 Tupper, Montréal, Québec H3H 1P3,
Canada and the ¶ Lady Davis Institute, McGill University,
Montréal, Québec H3H 1P3, Canada
9). In addition, differential
intracellular/surface partitioning was studied with co-transfection of
the alleles fused to distinct fluorescent proteins in COS-1 cells. By
quantitative confocal microscopy we found a higher ratio of cell
surface/total CTLAThr17 versus
CTLAAla17 (p = 0.01). Our findings
corroborate observations, in other proteins, that the signal peptide
can determine the efficiency of post-translational modifications other
than cleavage and suggest inefficient processing of the autoimmunity
predisposing Ala allele as the explanation for the genetic effect.
*
This work was supported in part by the Juvenile Diabetes
Research Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Pediatric
Endocrinology, McGill University Health Center, 2300 Tupper,
Montréal, Québec H3H 1P3, Canada. Tel.:
514-412-4315; Fax: 514-412-4264; E-mail:
constantin.polychronakos@mcgill.ca.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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