Hermes-Lima M et al. (2002) Comp Biochem Physiol C Toxicol Pharmacol "Animal response to drastic changes in oxygen availability and physiological oxidative stress."

Zenteno-Savi\;n T, Hermes-Lima M

[Comp Biochem Physiol C Toxicol Pharmacol, 2002]

Oxygen is essential for most life forms, but it is also inherently toxic due to its biotransformation into reactive oxygen species (ROS). In fact, the development of many animal and plant pathological conditions, as well as natural aging, is associated with excessive ROS production and/or decreased antioxidant capacity. However, a number of animal species are able to tolerate, under natural conditions, situations posing a large potential for oxidative stress. Situations range from anoxia in fish, frogs and turtles, to severe hypoxia in organs of freeze-tolerant snakes, frogs and insect larvae, or diving seals and turtles, and mild hypoxia in organs of dehydrated frogs and toads or estivating snails. All situations are reminiscent of ischemia/reperfusion events that are highly damaging to most mammals and birds. This article reviews the responses of anoxia/hypoxia-tolerant animals when subjected to environmental and metabolic stresses leading to oxygen limitation. Abrupt changes in metabolic rate in ground squirrels arousing from hibernation, as well as snails arousing from estivation, may also set up a condition of increased ROS formation. Comparing the responses from these diverse animals, certain patterns emerge. The most commonly observed response is an enhancement of the antioxidant defense. The increase in the baseline activity of key antioxidant enzymes, as well as ''secondary'' enzymatic defenses, and/or glutathione levels in preparation for a putative oxidative stressful situation arising from tissue reoxygenation seem to be the preferred evolutionary adaptation. Increasing the overall antioxidant capacity during anoxia/hypoxia is of relevance for species such as garter snakes (Thamnophis sirtalis parietalis) and wood fogs (Rana sylvatica), while diving freshwater turtles (Trachemys scripta elegans) appear to rely mainly upon high constitutive activities of antioxidant enzymes to deal with oxidative stress arising during tissue reoxygenation. The possibility that some animal species might control post-anoxic ROS generation cannot be excluded.

Bommireddy R et al. (2007) Trends Mol Med "TGFbeta1 and Treg cells: alliance for tolerance."

Bommireddy R, Doetschman T

[Trends Mol Med, 2007]

Transforming growth factor beta1 (TGFbeta1), an important pleiotropic, immunoregulatory cytokine, uses distinct signaling mechanisms in lymphocytes to affect T-cell homeostasis, regulatory T (T(reg))-cell and effector-cell function and tumorigenesis. Defects in TGFbeta1 expression or its signaling in T cells correlate with the onset of several autoimmune diseases. TGFbeta1 prevents abnormal T-cell activation through the modulation of Ca(2+)-calcineurin signaling in a Caenorhabditis elegans Sma and Drosophila Mad proteins (SMAD)3 and SMAD4-independent manner; however, in T(reg) cells, its effects are mediated, at least in part, through SMAD signaling. TGFbeta1 also acts as a pro-inflammatory cytokine and induces interleukin (IL)-17-producing pathogenic T-helper cells (T(h) IL-17 cells) synergistically during an inflammatory response in which IL-6 is produced. Here, we will review TGFbeta1 and its signaling in T cells with an emphasis on the regulatory arm of immune tolerance.

Schachter H (2009) Carbohydr Res "Paucimannose N-glycans in Caenorhabditis elegans and Drosophila melanogaster."

Schachter H

[Carbohydr Res, 2009]

There is a rich diversity of paucimannose N-glycans in worms and flies, and these may play a role in the survival of these organisms. Although paucimannose N-glycans are not expressed in vertebrates, complex N-glycans may take over some of the functions of paucimannose N-glycans. Identification of the target proteins of beta-1,2-N-acetylglucosaminyltransferase I (GnTI) in worms and flies and elucidation of their functions may thus lead to a better understanding of the role of GnTI-dependent glycoproteins in the survival/longevity of both invertebrates and vertebrates.

Schachter H (2009) Trends Glycosci Glycotechnol "The functions of paucimannose N-glycans in Caenorhabditis elegans"

Schachter H

[Trends Glycosci Glycotechnol, 2009]

Caenorhabditis elegans makes about 150 individual N-glycan structures. This review discusses the synthesis and possible functions of the paucimannose N-glycans that are highly abundant in invertebrates but not in vertebrates. The complexity of the worm's N-glycans is due in part to a variety of unusual fucosylation reactions and the addition of phosphorylcholine. Phosphorylcholine has been recognized as a widespread antigenic determinant in many important disease-causing parasites. The synthesis of paucimannose N-glycans depends on the prior action of UDP-GlcNAc:alpha 3-D-mannoside beta 1,2-N-acetylglucosaminyltransferase I (GnTI, encoded by Mgat1). There are three GnTI isoenzymes in the worm (GLY-12, GLY-13, GLY-14). Each GnTI isoenzyme has a distinct set of target proteins and a distinct role in the interaction of C.elegans with pathogenic bacteria. Identification of the protein substrates of GnTI in worms and elucidation of their functions may lead to a better understanding of the role of GnTI-dependent glycoproteins in the survival of both invertebrates and vertebrates.

Polevoda B et al. (2003) J Mol Biol "N-terminal acetyltransferases and sequence requirements for N-terminal acetylation of eukaryotic proteins."

Polevoda B, Sherman F

[J Mol Biol, 2003]

N(alpha)-terminal acetylation occurs in the yeast Saccharomyces cerevisiae by any of three N-terminal acetyltransferases (NAT), NatA, NatB, and NatC, which contain Ard1p, Nat3p and Mak3p catalytic subunits, respectively. The N-terminal sequences required for N-terminal acetylation, i.e. the NatA, NatB, and NatC substrates, were evaluated by considering over 450 yeast proteins previously examined in numerous studies, and were compared to the N-terminal sequences of more than 300 acetylated mammalian proteins. In addition, acetylated sequences of eukaryotic proteins were compared to the N termini of 810 eubacterial and 175 archaeal proteins, which are rarely acetylated. Protein orthologs of Ard1p, Nat3p and Mak3p were identified with the eukaryotic genomes of the sequences of model organisms, including Caenorhabditis elegans, Drosophila melanogaster, Arabidopsis thaliana, Mus musculus and Homo sapiens. Those and other putative acetyltransferases were assigned by phylogenetic analysis to the following six protein families: Ard1p; Nat3p; Mak3p; CAM; BAA; and Nat5p. The first three families correspond to the catalytic subunits of three major yeast NATs; these orthologous proteins were identified in eukaryotes, but not in prokaryotes; the CAM family include mammalian orthologs of the recently described Camello1 and Camello2 proteins whose substrates are unknown; the BAA family comprise bacterial and archaeal putative acetyltransferases whose biochemical activity have not been characterized; and the new Nat5p family assignment was on the basis of putative yeast NAT, Nat5p (YOR253W). Overall patterns of N-terminal acetylated proteins and the orthologous genes possibly encoding NATs suggest that yeast and higher eukaryotes have the same systems for N-terminal acetylation.

Gao F et al. (2014) Front Physiol "Trichinella spiralis, potential model nematode for epigenetics and its implication in metazoan parasitism."

Gao F, Wang R, Liu M

[Front Physiol, 2014]

The recent discovery of DNA methylation in the nematode T.spiralis may raise the possibility of using it as a potential model organism for epigenetic studies instead of C. elegans, which is deficient in this important epigenetic modification. In contrast to the free-living nematode C. elegans, T. spiralis is a parasitic worm that possesses a complicated life cycle and undergoes a complex developmental regulation of genes. We emphasize that the differential methylomes in the different life-history stages of T. spiralis can provide insight on how DNA methylation is triggered and regulated. In particular, we have demonstrated that DNA methylation is involved in the regulation of its parasitism-related genes. Further computational analyses indicated that the regulatory machinery for DNA methylation can also be found in the T. spiralis genome. By a logical extension of this point, we speculate that comprehensively addressing the epigenetic machinery of T. spiralis may help to understand epigenetics in invertebrates. Furthermore, considering the implication of epigenetics in metazoan parasitism, using T. spiralis as an epigenetic model organism may further contribute to drug development against metazoan parasites.

Paschinger K et al. (2008) Carbohydr Res "The N-glycosylation pattern of Caenorhabditis elegans."

Rendi D, Gutternigg M, Paschinger K, Wilson IB

[Carbohydr Res, 2008]

Determining the exact nature of N-glycosylation in Caenorhabditis elegans, a nematode worm and genetic model organism, has proved to have been an unexpected challenge in recent years; a wide range of modifications of its N-linked oligosaccharides have been proposed on the basis of structural and genomic analysis. Particularly mass spectrometric studies by a number of groups, as well as the characterisation of recombinant enzymes, have highlighted those aspects of N-glycosylation that are conserved in animals, those which are seemingly unique to this species and those which are shared with parasitic nematodes. These data, of importance for therapeutic developments, are reviewed.

Chuang HC et al. (2019) J Biomed Sci "MAP4K3/GLK in autoimmune disease, cancer and aging."

Chuang HC, Tan TH

[J Biomed Sci, 2019]

MAP4K3 (also named GLK) is a serine/threonine kinase, which belongs to the mammalian Ste20-like kinase family. At 22years of age, GLK was initially cloned and identified as an upstream activator of the MAPK JNK under an environmental stress and proinflammatory cytokines. The data derived from GLK-overexpressing or shRNA-knockdown cell lines suggest that GLK may be involved in cell proliferation through mTOR signaling. GLK phosphorylates the transcription factor TFEB and retains TFEB in the cytoplasm, leading to inhibition of cell autophagy. After generating and characterizing GLK-deficient mice, the important in vivo roles of GLK in T-cell activation were revealed. In T cells, GLK directly interacts with and activates PKC through phosphorylating PKC at Ser-538 residue, leading to activation of IKK/NF-B. Thus, GLK-deficient mice display impaired T-cell-mediated immune responses and decreased inflammatory phenotypes in autoimmune disease models. Consistently, the percentage of GLK-overexpressing T cells is increased in the peripheral blood from autoimmune disease patients; the GLK-overexpressing T cell population is correlated with disease severity of patients. The pathogenic mechanism of autoimmune disease by GLK overexpression was unraveled by characterizing T-cell-specific GLK transgenic mice and using biochemical analyses. GLK overexpression selectively promotes IL-17A transcription by inducing the AhR-RORt complex in T cells. In addition, GLK overexpression in cancer tissues is correlated with cancer recurrence of human lung cancer and liver cancer; the predictive power of GLK overexpression for cancer recurrence is higher than that of pathologic stage. GLK directly phosphorylates and activates IQGAP1, resulting in induction of Cdc42-mediated cell migration and cancer metastasis. Furthermore, treatment of GLK inhibitor reduces disease severity of mouse autoimmune disease models and decreases IL-17A production of human autoimmune T cells. Due to the inhibitory function of HPK1/MAP4K1 in T-cell activation and the promoting effects of GLK on tumorigenesis, HPK1 and GLK dual inhibitors could be useful therapeutic drugs for cancer immunotherapy. In addition, GLK deficiency results in extension of lifespan in Caenorhabditis elegans and mice. Taken together, targeting MAP4K3 (GLK) may be useful for treating/preventing autoimmune disease, cancer metastasis/recurrence, and aging.

Schachter H et al. (2002) Biochem Soc Symp "Functional post-translational proteomics approach to study the role of N-glycans in the development of Caenorhabditis elegans."

Spence AM, Rosa JC, Schachter H, Reinhold VN, Fan XL, Chen SH, Zhang WL, Callahan JW, Mahuran DJ, Bagshaw RD, She YM, Zhu SX

[Biochem Soc Symp, 2002]

Glycosylation is one of the most common post-translational protein modifications. Carbohydrate-mediated interactions between cells and their environment are important in differentiation, embryogenesis, inflammation, cancer and metastasis and other processes. Humans and mice with mutations that prevent normal N-glycosylation show multi-systemic defects in embryogenesis, thereby proving that these molecules are essential for normal development; however, a large number of proteins undergo defective glycosylation in these human and mouse mutants, and it is therefore difficult to determine the precise molecular roles of specific N-glycans on individual proteins. We describe here a 'functional post-translational proteomics' approach that is designed to determine the role of N-glycans on individual glycoproteins in the development of Caenorhabditis elegans.

Luo GZ et al. (2015) Nat Rev Mol Cell Biol "DNA N(6)-methyladenine: a new epigenetic mark in eukaryotes?"

He C, Blanco MA, Luo GZ, Greer EL, Shi Y

[Nat Rev Mol Cell Biol, 2015]

DNA N(6)-adenine methylation (N(6)-methyladenine; 6mA) in prokaryotes functions primarily in the host defence system. The prevalence and significance of this modification in eukaryotes had been unclear until recently. Here, we discuss recent publications documenting the presence of 6mA in Chlamydomonas reinhardtii, Drosophila melanogaster and Caenorhabditis elegans; consider possible roles for this DNA modification in regulating transcription, the activity of transposable elements and transgenerational epigenetic inheritance; and propose 6mA as a new epigenetic mark in eukaryotes.