H2O2, a Necessary Evil for Cell Signaling Rhee, Sue Goo
Science (American Association for the Advancement of Science),
06/2006, Letnik:
312, Številka:
5782
Journal Article
Recenzirano
Once considered lethal to cells, reactive oxygen species are now known to be involved in redox signaling pathways that may contribute to normal cell function as well as disease progression. New areas ...of research are emerging as to how the cells spatially and temporally channel hydrogen peroxide into specific signaling pathways to achieve desired cellular outcomes.
Peroxiredoxins (Prxs) constitute a major family of peroxidases, with mammalian cells expressing six Prx isoforms (PrxI to PrxVI). Cells produce hydrogen peroxide (H
2
O
2
) at various intracellular ...locations where it can serve as a signaling molecule. Given that Prxs are abundant and possess a structure that renders the cysteine (Cys) residue at the active site highly sensitive to oxidation by H
2
O
2
, the signaling function of this oxidant requires extensive and highly localized regulation. Recent findings on the reversible regulation of PrxI through phosphorylation at the centrosome and on the hyperoxidation of the Cys at the active site of PrxIII in mitochondria are described in this review as examples of such local regulation of H
2
O
2
signaling. Moreover, their high affinity for and sensitivity to oxidation by H
2
O
2
confer on Prxs the ability to serve as sensors and transducers of H
2
O
2
signaling through transfer of their oxidation state to bound effector proteins.
Peroxiredoxins (Prxs) are a family of peroxidases that reduce peroxides, with a conserved cysteine residue (the peroxidatic Cys) serving as the site of oxidation by peroxides. Peroxides oxidize the ...peroxidatic Cys-SH to Cys-SOH, which then reacts with another cysteine residue (typically the resolving Cys C(R)) to form a disulfide that is subsequently reduced by an appropriate electron donor. On the basis of the location or absence of the C(R), Prxs are classified into 2-Cys, atypical 2-Cys, and 1-Cys Prx subfamilies. In addition to their peroxidase activity, members of the 2-Cys Prx subfamily appear to serve as peroxide sensors for other proteins and as molecular chaperones. During catalysis, the peroxidatic Cys-SOH of 2-Cys Prxs is occasionally further oxidized to Cys-SO(2)H before disulfide formation, resulting in inactivation of peroxidase activity. This hyperoxidation, which is reversed by the ATP-dependent enzyme sulfiredoxin, modulates the sensor and chaperone functions of 2-Cys Prxs. The peroxidase activity of 2-Cys Prxs is extensively regulated via tyrosine and threonine phosphorylation, which allows modulation of the local concentration of the intracellular messenger H(2)O(2). Finally, 2-Cys Prxs interact with a variety of proteins, with such interaction having been shown to modulate the function of the binding partners in a reciprocal manner.
The observation that purified yeast glutamine synthetase is rapidly inactivated in a thiol-containing buffer yet retains activity in crude extracts containing the same thiol led to our discovery of ...an enzyme that protects against oxidation in a thiol-containing system. This novel antioxidant enzyme was shown to reduce hydroperoxides and, more recently, peroxynitrite with the use of electrons provided by a physiological thiol like thioredoxin. It defined a family of proteins, present in organisms from all kingdoms, that was named peroxiredoxin (Prx). All Prx enzymes contain a conserved Cys residue that undergoes a cycle of peroxide-dependent oxidation and thiol-dependent reduction during catalysis. Mammalian cells express six isoforms of Prx (Prx I to VI), which are classified into three subgroups (2-Cys, atypical 2-Cys, and 1-Cys) based on the number and position of Cys residues that participate in catalysis. The relative abundance of Prx enzymes in mammalian cells appears to protect cellular components by removing the low levels of peroxides produced as a result of normal cellular metabolism. During catalysis, the active site cysteine is occasionally overoxidized to cysteine sulfinic acid. Contrary to the general belief that oxidation to the sulfinic state is an irreversible process in cells, studies on the fate of the overoxidized Prx species revealed a mechanism by which the catalytically active thiol form is recovered. This sulfinic reduction is a slow, ATP-dependent process that is specific to 2-Cys Prx isoforms. This reversible overoxidation may represent an adaptation unique to eukaryotic cells that accommodates the intracellular messenger function of H
2O
2, but experimental validation of such speculation is yet to come.
Reactive oxygen species are not only harmful agents that cause oxidative damage in pathologies, they also have important roles as regulatory agents in a range of biological phenomena. The relatively ...recent development of this more nuanced view presents a challenge to the biomedical research community on how best to assess the significance of reactive oxygen species and oxidative damage in biological systems. Considerable progress is being made in addressing these issues, and here we survey some recent developments for those contemplating research in this area.
Sestrins (Sesns) protect cells from oxidative stress. The mechanism underlying the antioxidant effect of Sesns has remained unknown, however. The Nrf2-Keap1 pathway provides cellular defense against ...oxidative stress by controlling the expression of antioxidant enzymes. We now show that Sesn1 and Sesn2 interact with the Nrf2 suppressor Keap1, the autophagy substrate p62, and the ubiquitin ligase Rbx1 and that the antioxidant function of Sesns is mediated through activation of Nrf2 in a manner reliant on p62-dependent autophagic degradation of Keap1. Sesn2 was upregulated in the liver of mice subjected to fasting or subsequent refeeding with a high-carbohydrate, fat-free diet, whereas only refeeding promoted Keap1 degradation and Nrf2 activation, because only refeeding induced p62 expression. Ablation of Sesn2 blocked Keap1 degradation and Nrf2 activation induced by refeeding and thereby increased the susceptibility of the liver to oxidative damage resulting from the acute stimulation of lipogenesis associated with refeeding.
► Sestrins activate the Nrf2 pathway by promoting the autophagic degradation of Keap1 ► Keap1 degradation is fully dependent on the autophagy substrate p62 ► Keap1 degradation occurs in mice fed with high-carbohydrate, fat-free diets after fasting ► Sestrin2-deficient mice are susceptible to ROS damage resulting from the refeeding
Eleven distinct isoforms of phosphoinositide-specific phospholipase C (PLC),
which are grouped into four subfamilies (β, γ, δ, and
∍), have been identified in mammals. These isozymes catalyze the
...hydrolysis of phosphatidylinositol 4,5-bisphosphate PtdIns(4,5)P
2
to inositol 1,4,5-trisphosphate and diacylglycerol in response to the
activation of more than 100 different cell surface receptors. All PLC isoforms
contain X and Y domains, which form the catalytic core, as well as various
combinations of regulatory domains that are common to many other signaling
proteins. These regulatory domains serve to target PLC isozymes to the vicinity
of their substrate or activators through protein-protein or protein-lipid
interactions. These domains (with their binding partners in parentheses or
brackets) include the pleckstrin homology (PH) domain PtdIns(3)P,
βγ subunits of G proteins and the COOH-terminal region including
the C2 domain (GTP-bound α subunit of G
q
) of PLC-β; the
PH domain PtdIns(3,4,5)P
3
and Src homology 2 domain
tyrosine-phosphorylated proteins, PtdIns(3,4,5)P
3
of PLC-γ;
the PH domain PtdIns(4,5)P
2
and C2 domain (Ca
2+
)
of PLC-δ; and the Ras binding domain (GTP-bound Ras) of PLC-∍. The
presence of distinct regulatory domains in PLC isoforms renders them
susceptible to different modes of activation. Given that the partners that
interact with these regulatory domains of PLC isozymes are generated or
eliminated in specific regions of the cell in response to changes in receptor
status, the activation and deactivation of each PLC isoform are likely highly
regulated processes.
Celotno besedilo
Dostopno za:
CMK, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mitochondria produce hydrogen peroxide (H2O2) during energy metabolism in most mammalian cells as well as during the oxidation of cholesterol associated with the synthesis of steroid hormones in ...steroidogenic cells. Some of the H2O2 produced in mitochondria is released into the cytosol, where it serves as a key regulator of various signaling pathways. Given that mitochondria are equipped with several H2O2-eliminating enzymes, however, it had not been clear how mitochondrial H2O2 can escape destruction by these enzymes for such release. Peroxiredoxin III (PrxIII) is the most abundant and efficient H2O2-eliminating enzyme in mitochondria of most cell types. We found that PrxIII undergoes reversible inactivation through hyperoxidation of its catalytic cysteine residue to cysteine sulfinic acid, and that release of mitochondrial H2O2 likely occurs as a result of such PrxIII inactivation. The hyperoxidized form of PrxIII (PrxIII–SO2H) is reduced and reactivated by sulfiredoxin (Srx). We also found that the amounts of PrxIII–SO2H and Srx undergo antiphasic circadian oscillation in mitochondria of the adrenal gland, heart, and brown adipose tissue of mice maintained under normal conditions. Cytosolic Srx was found to be imported into mitochondria via a mechanism that requires formation of a disulfide-linked complex with heat shock protein 90, which is likely promoted by H2O2 released from mitochondria. The imported Srx was found to be degraded by Lon protease in a manner dependent on PrxIII hyperoxidation state. The coordinated import and degradation of Srx underlie Srx oscillation and consequent PrxIII–SO2H oscillation in mitochondria. The rhythmic change in the amount of PrxIII–SO2H suggests that mitochondrial release of H2O2 is also likely a circadian event that conveys temporal information on steroidogenesis in the adrenal gland and on energy metabolism in heart and brown adipose tissue to cytosolic signaling pathways.
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•H2O2 molecules released from mitochondria regulate various signaling pathways.•PrxIII is the most critical H2O2-removing enzyme in the mitochondria of most tissues.•H2O2 release occurs as a result of PrxIII hyperoxidation (inactivation) to Prx-SO2H.•The Prx-SO2H-reactivating enzyme Srx is imported into and degraded in mitochondria.•The import and degradation of Srx determine the circadian rhythm of H2O2 release.
Overview on Peroxiredoxin Rhee, Sue Goo
Molecules and cells,
01/2016, Letnik:
39, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Peroxiredoxins (Prxs) are a very large and highly conserved family of peroxidases that reduce peroxides, with a conserved cysteine residue, designated the "peroxidatic" Cys (CP) serving as the site ...of oxidation by peroxides (Hall et al., 2011; Rhee et al., 2012). Peroxides oxidize the CP-SH to cysteine sulfenic acid (CP-SOH), which then reacts with another cysteine residue, named the "resolving" Cys (CR) to form a disulfide that is subsequently reduced by an appropriate electron donor to complete a catalytic cycle. This overview summarizes the status of studies on Prxs and relates the following 10 minireviews.
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