October 2013

Thematic review series: redox-active protein modifications and signaling

Cover of JBC thematic series on redox-activate protein modifications and signalingSignal transduction is complex. As electrons fly between players in a signaling pathway, protein conformations change, which renders them amenable to interactions with other proteins. And eventually an extracellular message reaches the nucleus, and gene expression takes place. Or not.
In view of the large-scale phenotypic changes that signal transduction can bring about, it is easy to forget that the script of some of these changes is written in the most basic and ancient of chemical reactions: that of oxidation and reduction. In that sense, The Journal of Biological Chemistry’s recent series of thematic minireviews, organized by Associate Editor Ruma Banerjee at the University of Michigan Medical School, is a return to basics: a reminder that the cell accomplishes tasks of great complexity by keeping things simple.
First up in the series is an examination of the biological chemistry of peroxynitrite. A reactive nitrogen species, peroxynitrite is formed by the union of superoxide and nitric oxide radicals. It is implicated in a variety of biological contexts, such as the oxidation of thiol groups found on cysteine residues as well as direct one-electron oxidations, such as those of cytochrome c2+. The cellular pathology seen in neurodegenerative and inflammatory disease conditions is attributed largely to peroxynitrite-mediated nitration and oxidation of vascular wall components and vital signaling molecules. On the other hand, the use of intraphagosomal peroxynitrite by macrophages to eliminate phagocytized moieties is an effective way a cellular toxicant also may be channeled to do good. Author Rafael Radi rightly has christened peroxynitrite a “stealth” oxidant: The species is formed under fortuitous circumstances but exerts potent and far-reaching effects.
The next piece in the series celebrates the versatility of post-translational modifications of cysteine residues via the process of S-nitrosylation. The transfer of a nitroso group onto reduced cysteine residues exemplifies S-nitrosylation and yields S-nitrosocysteine, a species that is both an intermediary and a regulator of NO-induced signaling pathways. Given the sheer diversity of organ systems and physiological conditions that are affected by NO-mediated signaling, Harry Ischiropolous and his co-authors wisely ask if there is a selective mechanism that dictates the S-nitrosylation of different proteins. If so, what is this mechanism? Is it a mechanism influenced by certain structural cues found on the proteins involved, or could the other amino acids in the milieu be facilitators of S-nitrosylation over other post-translational cysteine modifications? The proteomic approach this minireview takes provides a big-picture view of not just S-nitrosylation but also the influences that post-translational modifications may exert on each other.
The theme of post-translational cysteine modifications and redox regulation of signal transduction continues in the third minireview in the series, where Mauro Lo Conte and Kate Carroll take up the cause of cysteine sulfenylation and sulfinylation. The ephemeral nature of the sulfenyl group makes it a sensitive, rapidly responding redox switch that modulates the activity of protein tyrosine kinases and phosphatases and ubiquitinylating and SUMO-ylating enzymes as well as transcription factors. That sulfenylation effectively stage manages cell signaling propagated by the epidermal growth factor family of ligands is revealing of its importance in maintaining homeostasis. Sulfinylation, on the other hand, appears to have a more specific role in the regulation of the antioxidant peroxiredoxin enzymes.
A primary reason cysteine is special among the amino acids lies in its ability to form disulfide bridges via the oxidation of its sulfhydryl group. As important as disulfide bridges are to maintaining the structural integrity of a protein, they can, as authors Claudia Cremers and Ursula Jakob at the University of Michigan show in the next minireview, act as molecular switches reconciling the structural changes in proteins with the transduction of signals and/or gene expression. An excellent example of this is the zinc centers in proteins containing zinc-binding motifs. Once thought to be purely structural features, zinc centers are now revealing themselves to be regulatory hubs wherein oxidation of the cysteine thiols that coordinate the ion leads to zinc release and the formation of disulfide bridges. This brings about conformational changes in the protein which may, for example, enhance or detract from DNA binding and thus gene expression. Furthermore, reduction by thioredoxins and glutaredoxins lends the element of reversibility to disulfide bridge formation, enabling them to function as true switches.
Apart from disulfide bridges, thioredoxins and glutaredoxins also oversee the regulation of S-glutathionylation — the focus of the next minireview by Kenneth Tew and his co-authors at the Medical University of South Carolina. S-glutathionylation occurs in response to reactive oxygen and nitrogen species and so is an additional layer of control over the signaling processes that the latter may influence. For example, the S-glutathionylation of Fas under oxidative conditions enhances apoptosis. S-glutathionylation is a relatively uncommon cysteinyl modification, which places it in a unique echelon of disease biomarkers. And, indeed, changes in patterns of S-glutathionylation of proteins are correlated with incidence of inflammatory, neurodegenerative and cardiovascular diseases and cancer. As more putative S-glutathionylation candidates are unearthed, the mechanism is poised to be an important diagnostic marker in the pathogenesis of major diseases that plague this day and age.
Lest it be thought that redox signaling is important only in disease states, the next minireview, by Alessandra Stangherlin and Akhilesh Reddy at the University of Cambridge, makes a strong case for the involvement of redox signals in the regulation of circadian oscillations. Based on the studies cited in the minireview, it seems increasingly likely that the control of peroxiredoxin timekeeping may well rest within the redox state of ambient thiols. That circadian rhythms and the generation of ROS cross-regulate demonstrates that circadian and redox cycles are strongly linked.
Finally, the last piece in the minireview series, “The Redox Proteome,” by Young-Mi Go Kang and Dean Jones at Emory University, is a summative treatment of the themes of redox biology addressed in the series. Moreover, the article is a harbinger of the future of the field of redox biochemistry. While considerable attention has been paid to the redox activities of particular proteins, a systems-biology approach to uncovering what makes different sulfur switches tick will serve to reveal more not only about disease pathogenesis but about basic physiology itself.

Akshat SharmaAkshat Sharma (asharma28@wisc.edu) received his M.S. in microbiology from North Dakota State University and is a Ph.D. student in the department of medical microbiology and immunology at the University of Wisconsin, Madison. Read his blog at http://fasterkilltcell.wordpress.com/.

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