Ubiquitination entails the covalent but reversible attachment of the 76 amino acid protein ubiquitin to, in most cases, lysine residue on protein substrates. It can be classified into monoubiquitination, multi-monoubiquitination and polyubiquitination according to the number and topology of ubiquitin molecules that are conjugated to the substrate. Ubiquitin signaling plays an important role in essentially all cellular processes. For example, monoubiquitination alters protein activity and subcellular localization, K48 polyubiquitination targets substrates for proteasomal degradation and K63 or linear polyubiquitin (polyUb) chains serve as protein-protein interaction platforms to mediate signal transduction. Although ubiquitin linkage selective interactions have been studied in a case-by-case basis, proteome-wide interaction proteomics studies have not been described yet.
Employees working in the research group headed by Michiel Vermeulen, theme Cancer development and immune defense together with researchers working in the lab of Huib Ovaa and the LUMC now describe Ubiquitin Interactor Affinity enrichment-Mass Spectrometry (UbIA-MS), a quantitative interaction proteomics method which makes use of chemically synthesized diubiquitin linkages to enrich and identify ubiquitin linkage interactors from crude cell lysates. The researchers describe the first global, proteome-wide interaction landscape for ubiquitin signaling in multiple cell types. Amongst the main findings, the authors identify TAB2/3 as novel K6 diubiquitin interactors, and they characterize UCHL3 as a K27-linkage selective interactor that regulates K27 polyubiquitin chain formation in cells. Furthermore, the researchers describe a class of monoubiquitin and K6 diubiquitin interactors whose binding is induced upon induction of DNA damage. In the future, UbIA-MS will have broad applications in the ongoing efforts to decipher the complex language of ubiquitin signaling. This work was very recently published in the journal Molecular Cell.
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