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• W2010864258 abstract "During cellular stress, monoubiquitin is in demand due to the accumulation of misfolded proteins that require proteasomal degradation. Kimura et al., 2009Kimura Y. Yashiroda H. Kudo T. Koitabashi S. Murata S. Kakizuka A. Tanaka K. Cell. 2009; (this issue)PubMed Google Scholar now show in yeast that monoubiquitin levels are bolstered during stress conditions by downregulation of the protein Rfu1, an inhibitor of the deubiquitinating enzyme Doa4. During cellular stress, monoubiquitin is in demand due to the accumulation of misfolded proteins that require proteasomal degradation. Kimura et al., 2009Kimura Y. Yashiroda H. Kudo T. Koitabashi S. Murata S. Kakizuka A. Tanaka K. Cell. 2009; (this issue)PubMed Google Scholar now show in yeast that monoubiquitin levels are bolstered during stress conditions by downregulation of the protein Rfu1, an inhibitor of the deubiquitinating enzyme Doa4. Recent proteomic analyses have suggested that the majority of cellular proteins are at some point modified with ubiquitin (Peng et al., 2003Peng J. Schwartz D. Elias J.E. Thoreen C.C. Cheng D. Marsischky G. Roelofs J. Finley D. Gygi S.P. Nat. Biotechnol. 2003; 21: 921-926Crossref PubMed Scopus (1226) Google Scholar), which results either in proteasomal degradation or in altered function or subcellular localization. Given that monomeric ubiquitin is the currency for these transactions, a hefty stash of monoubiquitin is mandatory for maintaining cellular health. Yeast cells, for example, satisfy this demand by piggybacking ubiquitin biosynthesis onto ribosomal proteins in the form of fusion proteins. This is a winning strategy for nutrient-rich environments in which ribosomal proteins are synthesized in abundance. However, under stress conditions, ribosomal protein synthesis shuts down, lowering ubiquitin production along with it (Finley et al., 1987Finley D. Ozkaynak E. Varshavsky A. Cell. 1987; 48: 1035-1046Abstract Full Text PDF PubMed Scopus (612) Google Scholar). Because stress induces an abundance of misfolded proteins that require degradation via the proteasome, this decline in ubiquitin production could not come at a worse time. Fortunately, to balance the books under stress conditions, yeast cells invest in a backup ubiquitin gene, UBI4, which secures a sufficient supply of monoubiquitin. Apart from de novo synthesis, supplies of monoubiquitin are also replenished by recycling polyubiquitin through the action of deubiquitinating enzymes (DUBs), including Doa4, Ubp6, and Ubp14 (Leggett et al., 2002Leggett D.S. Hanna J. Borodovsky A. Crosas B. Schmidt M. Baker R.T. Walz T. Ploegh H. Finley D. Mol. Cell. 2002; 10: 495-507Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar, Papa and Hochstrasser, 1993Papa F.R. Hochstrasser M. Nature. 1993; 366: 313-319Crossref PubMed Scopus (338) Google Scholar). One might therefore suspect that DUB activity is subject to regulation under stress conditions. This prospect is now confirmed by Kimura et al., 2009Kimura Y. Yashiroda H. Kudo T. Koitabashi S. Murata S. Kakizuka A. Tanaka K. Cell. 2009; (this issue)PubMed Google Scholar reporting in this issue, who identify Rfu1 (regulator of free ubiquitin chains 1) as a regulator of the DUB Doa4 in the budding yeast Saccharomyces cerevisiae. Kimura and colleagues identified Rfu1, a protein of previously unknown function, in a high-copy suppressor screen of cdc48-3 mutants, which have growth defects presumably due to an imbalance in the ratio of monoubiquitin to polyubiquitin. Even in wild-type cells, overexpression of Rfu1 leads to accumulation of low-molecular-weight polymers of unanchored ubiquitin, whereas monoubiquitin is depleted. Cells in which the RFU1 gene is deleted, in turn, showed the opposite pattern: depletion of free ubiquitin chains and accumulation of monoubiquitin. These findings suggest that Rfu1 regulates the cellular balance between mono- and polyubiquitin. But how? Might a DUB be involved? These investigators made the connection with the realization that Rfu1 colocalizes to endosomes with only one of the 19 DUBs in yeast, Doa4. The pattern of ubiquitin accumulation in cells lacking Rfu1 is an exact mirror image of the pattern observed in doa4 mutants, which are marked by depletion of monoubiquitin and accumulation of free polyubiquitin chains. This finding suggested that Rfu1 is a potential negative regulator of Doa4, a conjecture that is supported by genetic experiments. Rfu1 also interacts physically with Doa4 in vivo. The interaction is apparently direct, as it can be reconstituted with purified proteins in vitro. Recombinant Rfu1 also inhibits the DUB activity of Doa4 that is directed at polyubiquitin chains attached at lysine 48 (K48) and K63. What is the physiological significance of the inhibition of Doa4 that is mediated by Rfu1? The authors approach this question by looking at cellular conditions that boost the demand for monoubiquitin. Many stress conditions lead to an increased load of misfolded proteins that need to be ubiquitinated and degraded by the proteasome. Indeed, polyubiquitinated proteins accumulate in heat-stressed yeast cells. Remarkably, however, this does not coincide with a corresponding depletion of monoubiquitin even after 60 min of heat stress. Instead, heat treatment causes the depletion of free polyubiquitin chains, a finding that raises the possibility that deconjugation of such chains replenishes stores of monoubiquitin. A series of elegant experiments then demonstrated that Doa4, at least in part, mediates this activity under stress conditions. Once again, overexpression of Rfu1 potently inhibits the capacity of Doa4 to restore levels of monoubiquitin. The latter finding provides a neat molecular explanation for the heat sensitivity of cells overexpressing Rfu1. How are the opposing activities of Rfu1 and Doa4 arbitrated during the response to heat stress? The answer is pleasing in its simplicity: Rfu1 mRNA and protein are downregulated, and Doa4 activity increases. This dual modulation assures the rapid increase in Doa4 activity necessary to secure a continuous supply of monoubiquitin during heat stress. What remains to be seen is how Rfu1 inhibits Doa4 activity. Based on the observations that Rfu1 binds directly to Doa4 and does not bind appreciably to K48- or K63-linked ubiquitin chains in vitro, Rfu1 could interfere directly with Doa4 DUB activity. However, even when Rfu1 is present in excess, the activity of Doa4 toward ubiquitin chains is not completely abrogated. These experiments suggest that Rfu1 may have a more complex mechanism of action than that of a simple stoichiometric inhibitor of Doa4. Could Rfu1 be an allosteric inhibitor of Doa4? Does Rfu1 contain a low-affinity binding site for ubiquitin that shields ubiquitin chains from the grasp of Doa4? Regardless of the exact molecular mechanism, the discovery of Rfu1, a natural DUB inhibitor, is a major step forward in understanding the complex ways in which cells ensure ubiquitin homeostasis (Figure 1). Another question concerns the significance of free polyubiquitin chains. Kimura et al. propose that free polyubiquitin chains are a reservoir that can be leveraged to supply monoubiquitin upon exposure to stress. However, securing polyubiquitin as a reservoir for monoubiquitin is unlikely to be the sole function of Rfu1-mediated Doa4 inhibition, given that sufficient monoubiquitin levels would be more easily maintained by a constitutive DUB. One therefore wonders whether free polyubiquitin chains protected by Rfu1 play additional roles. In unstressed cells, these chains may, for example, neutralize some members of the burgeoning family of polyubiquitin binding proteins. Intriguingly, Rfu1 has weak similarity to the mammalian DUBs AMSH and UBP8, but a human counterpart to Rfu1 remains elusive. It is clear from the work of Kimura et al. that one role of Rfu1 is to provide the stimulus needed to maintain the reservoir of ubiquitin during stressful times. It is reasonable to expect that similar mechanisms in other organisms will be identified that keep their ubiquitin economy on the right track. An Inhibitor of a Deubiquitinating Enzyme Regulates Ubiquitin HomeostasisKimura et al.CellMay 01, 2009In BriefThe dynamic and reversible process of ubiquitin modification controls various cellular activities. Ubiquitin exists as monomers, unanchored chains, or protein-conjugated forms, but the regulation of these interconversions remains largely unknown. Here, we identified a protein designated Rfu1 (regulator of free ubiquitin chains 1), which regulates intracellular concentrations of monomeric ubiquitins and free ubiquitin chains in Saccharomyces cerevisiae. Rfu1 functions as an inhibitor of Doa4, a deubiquitinating enzyme. Full-Text PDF Open Archive" @default.
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• W2010864258 title "Rfu1: Stimulus for the Ubiquitin Economy" @default.
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