Abstract
The human inhibitor of Bruton's tyrosine kinase isoform α (IBtkα) is a BTB protein encoded by the IBTK gene, which maps to chromosomal locus 6q14.1, a mutational hot spot in lymphoproliferative disorders. Here, we demonstrate that IBtkα forms a CRL3(IBTK) complex promoting its self-ubiquitylation. We identified the tumor suppressor Pdcd4 as IBtkα interactor and ubiquitylation substrate of CRL3(IBTK) for proteasomal degradation. Serum-induced degradation of Pdcd4 required both IBtkα and Cul3, indicating that CRL3(IBTK) regulated the Pdcd4 stability in serum signaling. By promoting Pdcd4 degradation, IBtkα counteracted the suppressive effect of Pdcd4 on translation of reporter luciferase mRNAs with stem-loop structured or unstructured 5'-UTR. IBtkα depletion by RNAi caused Pdcd4 accumulation and decreased the translation of Bcl-xL mRNA, a well known target of Pdcd4 repression. By characterizing CRL3(IBTK) as a novel ubiquitin ligase, this study provides new insights into regulatory mechanisms of cellular pathways, such as the Pdcd4-dependent translation of mRNAs.
Highlights
IBtk␣ is an uncharacterized protein belonging to the family of BTB proteins
Because S. pombe Btb1 interacts with Pcu3p, the yeast orthologue of human Cul3, and is substrate receptor of Pcu3p(Cul3)-based ubiquitin ligase [11, 14], we speculated that IBtk␣ could be a substrate receptor of human CRL3
In the context of the luciferase reporter system, these results indicated that IBtk␣ promoted translation with a preferential effect on mRNA endowed with stem loop structured 5Ј-UTR, being the IBtk␣ interaction domains with Pdcd4 and Cul3 required for this action
Summary
Results: IBtk␣ is the substrate receptor for a Cullin3-dependent ubiquitin ligase promoting ubiquitylation and proteasomal degradation of Pdcd. We identified the tumor suppressor Pdcd as IBtk␣ interactor and ubiquitylation substrate of CRL3IBTK for proteasomal degradation. By characterizing CRL3IBTK as a novel ubiquitin ligase, this study provides new insights into regulatory mechanisms of cellular pathways, such as the Pdcd4-dependent translation of mRNAs. Protein ubiquitylation is an essential process for proteasome-mediated degradation or signalosome recruitment of proteins in response to extracellular stimuli [1, 2]. BTB proteins bind to Cul via the BTB domain [11] and determine the substrate specificity of the ubiquitin ligase complex through an additional protein-protein interaction domain, including the MATH (meprin and TRAF homology) domain, Kelch (KLH) repeats, zinc fingers, or ankyrins [12].
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