Identification of two rate-limiting steps in the degradation of partially folded immunoglobulin light chains
Antibody monomers are produced from two immunoglobulin heavy chains and two light chains that are folded and assembled in the endoplasmic reticulum This process is assisted and monitored by components of the endoplasmic reticulum quality control machinery; an outcome made more fraught by the unusual...
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Published in | Frontiers in cell and developmental biology Vol. 10; p. 924848 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
Frontiers Media S.A
22.08.2022
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Subjects | |
Online Access | Get full text |
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Summary: | Antibody monomers are produced from two immunoglobulin heavy chains and two light chains that are folded and assembled in the endoplasmic reticulum This process is assisted and monitored by components of the endoplasmic reticulum quality control machinery; an outcome made more fraught by the unusual genetic machinations employed to produce a seemingly unlimited antibody repertoire. Proper functioning of the adaptive immune system is as dependent on the success of this operation, as it is on the ability to identify and degrade those molecules that fail to reach their native state. In this study, two rate-limiting steps were identified in the degradation of a non-secreted κ light chain. Both focus on the constant domain (C
L
), which has evolved to fold rapidly and very stably to serve as a catalyst for the folding of the heavy chain C
H
1 domain. The first hurdle is the reduction of the disulfide bond in the C
L
domain, which is required for retrotranslocation to the cytosol. In spite of being reduced, the C
L
domain retains structure, giving rise to the second rate-limiting step, the unfolding of this domain at the proteasome, which results in a stalled degradation intermediate. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Candace A. Hayes, MS3 Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States Chiara Giannone, Vita-Salute San Raffaele University, Italy Edited by: Daniel G. S. Capelluto, Virginia Tech, United States Present Address: Christina Oikonomou, Genmab, Utrecht, Netherlands This article was submitted to Signaling, a section of the journal Frontiers in Cell and Developmental Biology Reviewed by: Yanfen Liu, ShanghaiTech University, China |
ISSN: | 2296-634X 2296-634X |
DOI: | 10.3389/fcell.2022.924848 |