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American Journal of Respiratory Cell and Molecular Biology. Vol. 36, pp. 135-137, 2007
© 2007 American Thoracic Society
DOI: 10.1165/rcmb.2006-001ED

Editorial

A Classification Scheme for Redox-Based Modifications of Proteins

Michael T. Forrester and Jonathan S. Stamler

Duke University Medical Center, Durham, North Carolina

Reactive oxygen and nitrogen species (ROS and RNS, respectively), products of enzymes and cellular metabolism as well as naturally occurring environmental agents, are capable of producing a wide range of post-translational protein modifications. Extensive work during the past decade has identified cysteine, tyrosine, and tryptophan as principal loci of protein modification by ROS/RNS and has strengthened our understanding of the reaction pathways through which these modifications occur (note: other reactive electrophiles, including aldehydes, avicins, and lipid peroxides, may also react with Cys residues). Since protein modifications by ROS/RNS formally alter thiol redox state or otherwise involve redox chemistry, they are referred to as redox-based or redox-related.

The functional roles of these modifications in the context of cellular physiology and pathophysiology, however, are less well understood. As a rule of thumb, eukaryotic cellular signaling entails dynamic reversibility and is under enzymatic control. Contrary to common perception, the rule holds true to form in redox systems: multiple classes of enzymes precisely control the production and turnover of second messenger RNS/ROS as well as the resultant post-translational modifications (1, 2). The weight of evidence further indicates that physiological cellular signaling—that is, adequate for the spatiotemporal exactitude requisite in signal propagation, including precise targeting within and between multiple proteins comprising signaling cascades, dynamic reversibility, and operation over physiological time scales (typically milliseconds to minutes) (Table 1)—is effected principally through S-nitrosylation (1, 3), the adduction of a nitrogen monoxide group and cysteine thiol to form an S-nitrosothiol (SNO) (Figure 1). While RNS are necessary and sufficient to elicit SNO formation, a role for ROS in modulating SNO signaling is not excluded (1, 3).


Figure 1
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  		Figure 1. A continuum of redox-based modifications that relates form of modification to level of ROS/RNS exposure and functional consequence. Cysteine-, tyrosine-, and tryptophan-directed modifications are shown in context of physiologic signaling, stress/adaptive signaling, and maladaptive/injurious contexts. Reversible, post-translational modifications of protein cysteine thiol side chains (-SNO, -SOH, -SSG) convey the ubiquitous influence on cellular signal transduction of redox-active molecules. Alternative modifications of Tyr (nitration) and Trp as well as irreversible modifications of Cys (-SO2H, -SO3H) represent mainly oxidative and nitrosative stresses. It should be noted that reversible modifications also form during cellular stress and pathophysiology. Protein carbonyls and methionine sulfoxides (not shown) are mainly detected in pathophysiologic conditions. The indicated modifications, from left to right, are -SNO, S-nitrosothiol; -SOH, sulfenic acid; -SSG, disulfides, such as glutathione mixed disulfide; -SO2H, sulfinic acid; -SO3H, sulfonic acid; nitrotryptophan; and nitrotyrosine.

 

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  		TABLE 1. REDOX-BASED PHYSIOLOGICAL SIGNALING, STRESS SIGNALING, AND PATHOPHYSIOLOGY

 
More generally, both RNS and ROS can effect diverse redox-based modifications of overlapping targets (Figure 1). Although examples of such modifications of proteins that have been identified with cellular roles are too few to allow general assignments of function, it appears that signaling by ROS/RNS is primarily the purview of Cys residues (Figure 1). In particular, S-oxidative modifications of proteins that are reversible, stimulus-coupled, and enzymatically regulated may subserve primarily stress signaling in the context of adaptive responses, such as wound healing and cellular growth or hypertrophy (2) (Table 1). By contrast, the redox-based modifications of proteins that are neither precisely regulated nor reversible will generally exert deleterious effects. It is readily apparent that the assignment of physiologic relevance presents a fundamental challenge in redox systems, not the least because the same redox-based modifications can have regulatory or pathophysiologic consequences in different cellular contexts. Three articles in this issue of AJRCMB highlight these interpretive challenges (4–6).

In considering these reports, the reader should ask: Are the modifications driven by noxious substances or by physiologic stimuli? Do the modifications subserve a physiologic homeostatic function or disrupt cellular processes? Are the redox-based modifications simply a function of intrinsic reactivity of ROS/RNS that results in protective or deleterious effects, or do they subserve cellular signaling? And to the extent that the redox regulation of protein function elicits cellular signals, are those signals: (1) physiologic and homeostatic (exemplified by the drive to breath, coupling of blood flow with metabolic demand, and regulation of the heart), (2) stress-related or adaptive (e.g., upregulation of protective genes, proliferative responses, increased release of calcium from internal stores of the failing heart), or (3) maladaptive/injurious, including growth signals with malignant potential and overt cellular injury? (See Table 1.)

Acknowledgments

The authors thank Douglas Hess for helpful discussions and for reviewing the manuscript.

Footnotes

This work was supported by NIEHS Grant U19 ES012496 (to J.S.S.).

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

References

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  2. Rhee SG. Cell signaling. H2O2, a necessary evil for cell signaling. Science 2006;312:1882–1883.[Abstract/Free Full Text]
  3. Foster MW, Hess DT, Stamler JS. S-nitrosylation TRiPs a calcium switch. Nat Chem Biol 2006;2:570–571.[CrossRef][Medline]
  4. Bove PF, Wesley UV, Greul AK, Hristova M, Dostmann WR, van der Vliet A. Nitric oxide promotes airway epithelial wound repair through enhanced activation of MMP-9. Am J Respir Cell Mol Biol 2006;36:138–146.
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  8. Wang G, Moniri NH, Ozawa K, Stamler JS, Daaka Y. Nitric oxide regulates endocytosis by S-nitrosylation of dynamin. Proc Natl Acad Sci USA 2006;103:1295–1300.[Abstract/Free Full Text]
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  11. Rizzo MA, Piston DW. Regulation of beta cell glucokinase by S-nitrosylation and association with nitric oxide synthase. J Cell Biol 2003;161:243–248.[Abstract/Free Full Text]
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