Wiggins, C. M., Tsvetkov, P., Johnson, M., Joyce, C. L., Lamb, C. A., Bryant, N. J., Komander, D., Shaul, Y. and Cook, S. J. (2011) BIMEL, an intrinsically disordered protein, is degraded by 20S proteasomes in the absence of poly-ubiquitylation. Journal of Cell Science, 124(6), pp. 969-977. (doi: 10.1242/jcs.058438)
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Publisher's URL: http://dx.doi.org/10.1242/jcs.058438
Abstract
BIM-extra long (BIMEL), a pro-apoptotic BH3-only protein and part of the BCL-2 family, is degraded by the proteasome following activation of the ERK1/2 signalling pathway. Although studies have demonstrated poly-ubiquitylation of BIMEL in cells, the nature of the ubiquitin chain linkage has not been defined. Using ubiquitin-binding domains (UBDs) specific for defined ubiquitin chain linkages, we show that BIMEL undergoes K48-linked poly-ubiquitylation at either of two lysine residues. Surprisingly, BIMEL Delta KK, which lacks both lysine residues, was not poly-ubiquitylated but still underwent ERK1/2-driven, proteasome-dependent turnover. BIM has been proposed to be an intrinsically disordered protein (IDP) and some IDPs can be degraded by uncapped 20S proteasomes in the absence of poly-ubiquitylation. We show that BIMEL is degraded by isolated 20S proteasomes but that this is prevented when BIMEL is bound to its pro-survival target protein MCL-1. Furthermore, knockdown of the proteasome cap component Rpn2 does not prevent BIMEL turnover in cells, and inhibition of the E3 ubiquitin ligase beta-TrCP, which catalyses poly-Ub of BIMEL, causes Cdc25A accumulation but does not inhibit BIMEL turnover. These results provide new insights into the regulation of BIMEL by defining a novel ubiquitin-independent pathway for the proteasome-dependent destruction of this highly toxic protein.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Bryant, Dr Nia |
Authors: | Wiggins, C. M., Tsvetkov, P., Johnson, M., Joyce, C. L., Lamb, C. A., Bryant, N. J., Komander, D., Shaul, Y., and Cook, S. J. |
College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
Journal Name: | Journal of Cell Science |
ISSN: | 0021-9533 |
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