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Reference: Chandra A, et al. (2010) Synthetic lethality of rpn11-1 rpn10Delta is linked to altered proteasome assembly and activity. Curr Genet 56(6):543-57

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Abstract

An rpn11-1 temperature-sensitive mutant shows defect in proteolysis, mitochondrial function and proteasome assembly. The Rpn11 protein is a proteasome subunit that deubiquitinates proteolytic substrates. Multiubiquitinated proteins interact with proteasome receptors, such as Rpn10, which intriguingly is also required for promoting proteasome stability. We report here that Rpn10 binds Rpn11, and genetic studies revealed synthetic lethality of an rpn11-1 rpn10Delta double mutant. The carboxy-terminus of Rpn11 is critical for function, as deletion of 7 C-terminal residues prevented suppression of rpn11-1 rpn10Delta. Native gel electrophoresis showed increased levels of the proteasome 20S catalytic particle in rpn11-1 rpn10Delta, and altered assembly. The inviability of rpn11-1 rpn10Delta was suppressed by rpn10(uim), a mutant that can bind the proteasome, but not multiubiquitin chains. rpn10(uim) reduced the levels of free 20S, and increased formation of intact proteasomes. In contrast, rpn10(vwa), which binds multiubiquitin chains but not the proteasome, failed to suppress rpn11-1 rpn10Delta. Moreover, high levels of multiubiquitinated proteins were bound to rpn10(vwa), but were not delivered to the proteasome. Based on these findings, we propose that the lethality of rpn11-1 rpn10Delta results primarily from altered proteasome integrity. It is conceivable that Rpn10/Rpn11 interaction couples proteasome assembly to substrate binding.

Reference Type
Journal Article | Research Support, N.I.H., Extramural
Authors
Chandra A, Chen L, Madura K
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