Control of cellular Bcl-xL levels by deamidation-regulated degradation = 디아미데이션에 의해 조절되는 분해에 의한 세포내 Bcl-xL 단백질의 조절

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Title
Control of cellular Bcl-xL levels by deamidation-regulated degradation = 디아미데이션에 의해 조절되는 분해에 의한 세포내 Bcl-xL 단백질의 조절
Author(s)
So Hee Dho; B E Deverman; C Lapid; S R Manson; L Gan; J J Riehm; R Aurora; Ki Sun Kwon; S J Weintraub
Bibliographic Citation
PLoS Biology, vol. 11, no. 6, pp. 1001588-1001588
Publication Year
2013
Abstract
The cellular concentration of Bcl-xL is among the most important determinants of treatment response and overall prognosis in a broad range of tumors as well as an important determinant of the cellular response to several forms of tissue injury. We and others have previously shown that human Bcl-xL undergoes deamidation at two asparaginyl residues and that DNA-damaging antineoplastic agents as well as other stimuli can increase the rate of deamidation. Deamidation results in the replacement of asparginyl residues with aspartyl or isoaspartyl residues. Thus deamidation, like phosphorylation, introduces a negative charge into proteins. Here we show that the level of human Bcl-xL is constantly modulated by deamidation because deamidation, like phosphorylation in other proteins, activates a conditional PEST sequence to target Bcl-xL for degradation. Additionally, we show that degradation of deamidated Bcl-xL is mediated at least in part by calpain. Notably, we present sequence and biochemical data that suggest that deamidation has been conserved from the simplest extant metazoans through the human form of Bcl-xL, underscoring its importance in Bcl-xL regulation. Our findings strongly suggest that deamidation-regulated Bcl-xL degradation is an important component of the cellular rheostat that determines susceptibility to DNA-damaging agents and other death stimuli.
ISSN
1544-9173
Publisher
Public Library of Science
DOI
http://dx.doi.org/10.1371/journal.pbio.1001588
Type
Article
Appears in Collections:
Division of Research on National Challenges > Aging Research Center > 1. Journal Articles
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