Inefficient assembly and intracellular accumulation of antibodies with mutations in V(H) CDR2.
J Immunol
; 160(12): 5963-70, 1998 Jun 15.
Article
em En
| MEDLINE
| ID: mdl-9637510
ABSTRACT
We previously described secretion defects in four mutants of the murine anti-phosphocholine Ab, T15. The mutant heavy (H) chains had amino acid replacements in the V(H) complementarity-determining region 2 (HCDR2) and were expressed at normal intracellular levels. Here, the intracellular fate of the secretion-defective mutant heavy chains was investigated. Metabolic labeling demonstrated that the T15 wild-type Ab was secreted within a 4-h chase. In contrast, the mutant H chains accumulated with intracellular t(1/2) values ranging from 10 to 24 h. The mutant H chains were associated with increased levels of the molecular chaperones BiP and GRP94, and remained endoglycosidase H sensitive, suggesting retention in the endoplasmic reticulum. Assembly of the mutant H chains with T15 light (L) chain was arrested at the H2 and H2L intermediate stages of the T15 wild-type pathway (H2 --> H2L --> H2L2). Even though some assembly with L chain occurred, it was not as a secretion-competent H2L2 Ig moiety. The T15 L chains coexpressed with mutant H chains were degraded efficiently except for a minor L chain population with a long t(1/2) that was apparently protected at the H2L stage. To our knowledge, this is the first study demonstrating that intracellular half-lives of Ig H and L chains can be influenced by somatic mutations in HCDR2.
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Base de dados:
MEDLINE
Assunto principal:
Autoantígenos
/
Região Variável de Imunoglobulina
/
Zíper de Leucina
/
Cadeias Pesadas de Imunoglobulinas
/
Proteínas de Ligação a DNA
Limite:
Animals
Idioma:
En
Ano de publicação:
1998
Tipo de documento:
Article