S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Tsang, Anthony H.; Lee, Yun I.L.; Ko, Han Seok; Savitt, Joseph M.; Pletniková, Olga; Troncoso, Juan C.; Dawson, Valina L.; Dawson, Ted M.; Chung, Kenny K.K.

doi:10.1073/pnas.0810595106

Cited by 144 publications

(120 citation statements)

References 34 publications

(36 reference statements)

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“…Previous studies showed that the higher levels of NO· generated by chemicals or by iNOS can induce apoptosis or necrosis (reviewed in references 6 and 36). Higher levels of NO· result in XIAP S-nitrosylation which consequently abolishes XIAP's anticaspase-3 activity (58).…”

Section: Discussionmentioning

confidence: 99%

Bacterium-Generated Nitric Oxide Hijacks Host Tumor Necrosis Factor Alpha Signaling and Modulates the Host Cell Cycle In Vitro

Mocca

Wang

2012

J Bacteriol

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In mammalian cells, nitric oxide (NO·) is an important signal molecule with concentration-dependent and often controversial functions of promoting cell survival and inducing cell death. An inducible nitric oxide synthase (iNOS) in various mammalian cells produces higher levels of NO· from L-arginine upon infections to eliminate pathogens. In this study, we reveal novel pathogenic roles of NO· generated by bacteria in bacterium-host cell cocultures using Moraxella catarrhalis, a respiratory tract disease-causing bacterium, as a biological producer of NO·. We recently demonstrated that M. catarrhalis cells that express the nitrite reductase (AniA protein) can produce NO· by reducing nitrite. Our study suggests that, in the presence of pathophysiological levels of nitrite, this opportunistic pathogen hijacks host cell signaling and modulates host gene expression through its ability to produce NO· from nitrite. Bacterium-generated NO· significantly increases the secretion of tumor necrosis factor alpha (TNF-␣) and modulates the expression of apoptotic proteins, therefore triggering host cell programmed death partially through TNF-␣ signaling. Furthermore, our study reveals that bacterium-generated NO· stalls host cell division and directly results in the death of dividing cells by reducing the levels of an essential regulator of cell division. This study provides unique insight into why NO· may exert more severe cytotoxic effects on fast growing cells, providing an important molecular basis for NO·-mediated pathogenesis in infections and possible therapeutic applications of NO·-releasing molecules in tumorigenesis. This study strongly suggests that bacterium-generated NO· can play important pathogenic roles during infections. In mammalian cells, nitric oxide (NO·) is a highly reactive and diffusible signaling molecule that plays key roles in modulating both physiological and pathological processes, such as immune response, cell survival, and cell death (reviewed in references 8 and 36). The diverse functions of NO· are often determined by its concentration or its source of production. Low levels of endogenous NO· are produced from L-arginine by constitutively expressed nitric oxide synthase in neuronal cells (nNOS, also known as NOS1) and endothelial cells (eNOS, also known as NOS3) to mediate normal physiological processes. Higher levels of NO· can be produced by an inducible nitric oxide synthase (iNOS, also known as NOS2) in different cell types, but mainly in macrophages, upon infection to kill pathogens (reviewed in reference 9). The higher levels of NO· produced by iNOS have been implicated in various human inflammatory diseases and neurodegenerative diseases (reviewed in references 9 and 12) and in chronic inflammation-related tumorigenesis (18, 33). Recent studies have also shown that chemical-generated higher levels of exogenous NO· can induce tumor cell apoptosis in vitro and in animal studies (37; reviewed in reference 1), raising interests in therapeutic exploration of NO·-releasing reagents as antitumor...

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Section: Discussionmentioning

confidence: 99%

Bacterium-Generated Nitric Oxide Hijacks Host Tumor Necrosis Factor Alpha Signaling and Modulates the Host Cell Cycle In Vitro

Mocca

Wang

2012

J Bacteriol

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“…The biotin switch assay for detecting the S-nitrosylation was performed as previously described (Tsang et al, 2009). Adult male mouse brain or HEK 293T cells overexpressing Cdk5 or its cysteine mutants were lysed in HENT buffer (250 mM HEPES, 1 mM EDTA, 0.1 mM neocuproine, 1% Triton X-100).…”

Section: Methodsmentioning

confidence: 99%

S-Nitrosylation of Cyclin-Dependent Kinase 5 (Cdk5) Regulates Its Kinase Activity and Dendrite Growth During Neuronal Development

Zhang¹,

Yu²,

Tsang³

et al. 2010

J. Neurosci.

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Precise regulation of cyclin-dependent kinase 5 (Cdk5), a member of the cyclin-dependent kinase family, is critical for proper neuronal development and functions. Cdk5 is activated through its association with the neuron-specific activator p35 or p39. Nonetheless, how its kinase activity is regulated in neurons is not well understood. In this study, we found that Cdk5 activity is regulated by S-nitrosylation, a post-translational modification of protein that affects a plethora of neuronal functions. S-nitrosylation of Cdk5 occurs at Cys83, which is one of the critical amino acids within the ATP-binding pocket of the kinase. Upon S-nitrosylation, Cdk5 exhibits reduced kinase activity, whereas mutation of Cys83 to Ala on Cdk5 renders the kinase refractory to such inhibition. Importantly, S-nitrosylated Cdk5 can be detected in the mouse brain, and blocking the S-nitrosylation of Cdk5 in cultured hippocampal neurons enhances dendritic growth and branching. Together, our findings reveal an important role of S-nitrosylation in regulating Cdk5 kinase activity and dendrite growth in neurons during development.

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“…Immunohistochemical studies suggest that XIAP may be partially associated with the pathogenesis of Parkinson's disease and dementia with Lewy bodies (Kawamoto et al, 2012). Interestingly, XIAP dysfunction resulting from S-nitrosylation has also been described in Parkinson's disease (Tsang et al, 2009). Also, transgenic expression of XIAP in neurons using the neuron-specific enolase promoter (nse-XIAP) improves prognosis in a mouse model of Parkinson's disease (Crocker et al, 2003).…”

mentioning

confidence: 99%

FAIM-L Is an IAP-Binding Protein That Inhibits XIAP Ubiquitinylation and Protects from Fas-Induced Apoptosis

et al. 2013

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The neuronal long isoform of Fas Apoptotic Inhibitory Molecule (FAIM-L) protects from death receptor (DR)-induced apoptosis, yet its mechanism of protection remains unknown. Here, we show that FAIM-L protects rat neuronal Type II cells from Fas-induced apoptosis. XIAP has previously emerged as a molecular discriminator that is upregulated in Type II and downregulated in Type I apoptotic signaling. We demonstrate that FAIM-L requires sustained endogenous levels of XIAP to protect Type II cells as well as murine cortical neurons from Fas-induced apoptosis. FAIM-L interacts with the BIR2 domain of XIAP through an IAP-binding motif, the mutation of which impairs the antiapoptotic function of FAIM-L. Finally, we report that FAIM-L inhibits XIAP auto-ubiquitinylation and maintains its stability, thus conferring protection from apoptosis. Our results bring new understanding of the regulation of endogenous XIAP by a DR antagonist, pointing out at FAIM-L as a promising therapeutic tool for protection from apoptosis in pathological situations where XIAP levels are decreased.

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S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Cited by 144 publications

References 34 publications

Bacterium-Generated Nitric Oxide Hijacks Host Tumor Necrosis Factor Alpha Signaling and Modulates the Host Cell Cycle In Vitro

Bacterium-Generated Nitric Oxide Hijacks Host Tumor Necrosis Factor Alpha Signaling and Modulates the Host Cell Cycle In Vitro

S-Nitrosylation of Cyclin-Dependent Kinase 5 (Cdk5) Regulates Its Kinase Activity and Dendrite Growth During Neuronal Development

FAIM-L Is an IAP-Binding Protein That Inhibits XIAP Ubiquitinylation and Protects from Fas-Induced Apoptosis

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