by Marilene Demasi
Protein polyubiquitination was first described as a post-translational modification to direct proteins for degradation. The ubiquitin molecule is covalently bound to the target protein and the polyubiquitin chain is created by successive attachments of ubiquitin through its carboxy-terminal Glycine mainly to Lysine48 (K48) residues of previously conjugated ubiquitin. Proteins tagged with a K48-linked polyubiquitin chain are directed for degradation. However, distinct ubiquitin chains are built up through other Lysine residues from ubiquitin, resulting in distinct structural patterns of ubiquitin complexes, which in most cases are unrelated to target protein degradation.
The role of the ubiquitin-proteasome system during the oxidative stress response has been investigated for decades. In particular, there are major controversies regarding the way that oxidized proteins are degraded, especially whether they are or are not polyubiquitinated. A work recently published by Silva et al. in Nat. Struct. Mol. Biol.  unravels a novel important mechanism of oxidative stress response regulated through the formation of Lysine 63 (K63)-based polyubiquitin chains. Using the yeast S. cerevisiae as model, the authors showed that K63-linked polyubiquitin chains specifically accumulate when cells are challenged with H₂O₂. Ribosomal proteins were identified as preferential targets of K63 polyubiquitination. Additionally, the deubiquitinating (DUB) enzyme Ubp2, which supports the hydrolysis of K63-linked ubiquitins, was identified as the redox sensor of such process.
Although an important class of DUBs is dependent on a reactive cysteine in the catalytic site, their reactivity towards pro-oxidants has been poorly explored. In this work, Ubp2 inactivation by H₂O₂ was shown to determine the maintenance of the K63-linked polyubiquitin chains, which in turn stabilize the ribosome. Ribosomal stabilization was demonstrated to ensure increased translation of proteins related to antioxidant defense (i.e., Thioredoxin1, Peroxiredoxin1, Glutaredoxin2, Glutaredoxin5) and of other stress-response proteins, such as chaperones.
These results provide an important novel element for consideration regarding models of redox-dependent cellular signaling.
Gustavo M. Silva, the first author of the publication, started his scientific career as undergraduate student at Luis E. S. Netto’s lab (Institute of Biosciences – USP), supervised by Marilene Demasi (Institute Butantan), both members of the Redoxoma network, followed by a Ph.D in the same group on the redox regulation of the 20S proteasome catalytic unit . He is presently a postdoctoral fellow at New York University. We are very pleased that his former training with our groups has provided relevant fruitful developments.
- G. M. Silva, D. Finley, C. Vogel.
K63 polyubiquitination is a new modulator of the oxidative stress response.
Nature Structural & Molecular Biology, 22: 116-23, 2015. | http://dx.doi.org/10.1038/nsmb.2955
- G. M. Silva, L. E. S. Netto, V. Simões, L. F. A. Santos, F. C. Gozzo, M. A. A. Demasi, C. L. P. Oliveira, R. N. Bicev, C. F. Klitzke, M. C. Sogayar, M. Demasi.
Redox Control of 20S Proteasome Gating.
Antioxidants & Redox Signaling, 16(11): 1183-94, 2012. | http://dx.doi.org/10.1089/ars.2011.4210
Marilene Demasi, PhD.
Professor at Laboratory of Biochemistry and Biophysics,
Butantan Institute, Brazil.