期刊
JOURNAL OF CELL SCIENCE
卷 124, 期 6, 页码 969-977出版社
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.058438
关键词
BIMEL; ERK1/2; Intrinsically disordered protein; 20S proteasome; Ubiquitin
类别
资金
- BBSRC [BB/E02162X/1]
- BBSRC/AstraZeneca
- BBSRC [BB/E02162X/1] Funding Source: UKRI
- MRC [MC_U105192732] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/E02162X/1, BBS/E/B/0000H151] Funding Source: researchfish
- Medical Research Council [MC_U105192732] Funding Source: researchfish
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.
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