Regulation of inducible nitric oxide synthase by aggresome formation

Kołodziejska, Katarzyna; Burns, Alan R.; Moore, Robert H.; Stenoien, David L.; Eissa, N. Tony

doi:10.1073/pnas.0500485102

Cited by 74 publications

(73 citation statements)

References 30 publications

(54 reference statements)

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“…Recent evidence suggests that aggresome formation is also a physiologic mechanism to regulate certain cellular proteins. The latter process, termed ''physiologic aggresome,'' has been described in connection to cellular regulation of iNOS (8,9). We have recently shown that iNOS is expressed initially as a cytosolic protein but is eventually targeted to a perinuclear location, identified by our data as an aggresome.…”

mentioning

confidence: 77%

“…In vivo, iNOS is expressed in states of inflammation and in response to proinflammatory cytokines (5,17). We have previously shown that cytokine-induced iNOS is targeted to the aggresome in various human and murine cell lines (8). In RT4 cells, an epithelial cell line in which iNOS production and iNOS aggresomes have been well characterized (16,18,19), iNOS aggresome formation becomes clearly evident 24 h following cytokine stimulation (8).…”

Section: Dar-4m Am Is a Reliable Indicator Of Subcellular No Productimentioning

confidence: 99%

“…We have previously shown that cytokine-induced iNOS is targeted to the aggresome in various human and murine cell lines (8). In RT4 cells, an epithelial cell line in which iNOS production and iNOS aggresomes have been well characterized (16,18,19), iNOS aggresome formation becomes clearly evident 24 h following cytokine stimulation (8). We investigated whether aggresomes formed by cytokine-induced iNOS would contain inactive iNOS.…”

Section: Dar-4m Am Is a Reliable Indicator Of Subcellular No Productimentioning

confidence: 99%

“…We have previously shown that cytokine-induced iNOS is sequestered in a perinuclear aggresome in various human and murine cell lines (8,9). Airway bronchial epithelial cells represent a major source of iNOS in the lung (17,20).…”

Section: Primary Normal Human Bronchial Epithelial Cells Form Aggresomesmentioning

confidence: 99%

“…We have previously shown that iNOS exists in 2 cellular compartments, the first being a diffuse cytosolic location and the second being a perinuclear compartment characterized as an iNOS aggresome, whose formation is accelerated by proteasomal inhibitors such as MG132 (8,9). Using live cell imaging and DAR, we monitored the subcellular NO production over various time points in HEK293-iNOS-GFP cells in which iNOS aggresome formation was accelerated by the proteasome inhibitor MG132 (Fig.…”

Section: Dar-4m Am Is a Reliable Indicator Of Subcellular No Productimentioning

confidence: 99%

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The physiologic aggresome mediates cellular inactivation of iNOS

Pandit

Kołodziejska

Zeng

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Nitric Oxide (NO), produced by inducible nitric oxide synthase (iNOS), has been implicated in the pathogenesis of various biological and inflammatory disorders. Recent evidence suggests that aggresome formation is a physiologic stress response not limited to misfolded proteins. That stress response, termed ''physiologic aggresome,'' is exemplified by aggresome formation of iNOS, an important host defense protein. The functional significance of cellular formation of the iNOS aggresome is hitherto unknown. In this study, we used live cell imaging, fluorescence microscopy, and intracellular fluorescence NO probes to map the subcellular location of iNOS and NO under various conditions. We found that NO production colocalized with cytosolic iNOS but aggresomes containing iNOS were distinctly devoid of NO production. Further, cells expressing iNOS aggresomes produced significantly less NO as compared with cells not expressing aggresomes. Importantly, primary normal human bronchial epithelial cells, stimulated by cytokines to express iNOS, progressively sequestered iNOS to the aggresome, a process that correlated with marked reduction of NO production. These results suggest that bronchial epithelial cells used the physiologic aggresome mechanism for iNOS inactivation. Our studies reveal a novel cellular strategy to terminate NO production via formation of the iNOS aggresome.misfolded ͉ nitric oxide ͉ primary cells ͉ proteasome ͉ degradation

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mentioning

confidence: 77%

Section: Dar-4m Am Is a Reliable Indicator Of Subcellular No Productimentioning

confidence: 99%

Section: Dar-4m Am Is a Reliable Indicator Of Subcellular No Productimentioning

confidence: 99%

Section: Primary Normal Human Bronchial Epithelial Cells Form Aggresomesmentioning

confidence: 99%

Section: Dar-4m Am Is a Reliable Indicator Of Subcellular No Productimentioning

confidence: 99%

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The physiologic aggresome mediates cellular inactivation of iNOS

Pandit

Kołodziejska

Zeng

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Redox Regulation of Protein Misfolding, Synaptic Damage, and Neuronal Loss in Neurodegenerative Diseases

Nakamura

Lipton

2011

Protein Chaperones and Protection From Neurodegenerative Diseases

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Inducible nitric oxide synthase: An asset to neutrophils

Saini

Singh

2018

Journal of Leukocyte Biology

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Neutrophils play a key role in innate immune responses against foreign intrusion and influence the subsequent instigation of adaptive immune response. Nitric oxide (NO) synthesized by neutrophil nitric oxide synthase (NOS) profoundly modulates their diverse physiological responsibilities furthermore encompassing pathological implications. Neutrophils are the active participants in diverse inflammatory and cardiovascular disorders but neutrophil nitric oxide synthase (NOS) remains enigmatic on various aspects. This review focuses on inducible NOS (iNOS) and makes an attempt to address its potential impact in neutrophil pathophysiology, their differentiation, functionality, and survival. We described the scenario from its expressional modulation, by pro-and anti-inflammatory cytokines governing the extent and duration of neutrophil immune response, to iNOS catalysis, the intracellular compartmentalization, and protein-protein interactions determining its microenvironment, activity and its contribution as a potential signaling protein apart from its role as signal transducer. Further, the relevance of investigating the unexplored facets of iNOS biology in neutrophils and possible prototypes of iNOS regulation is also exemplified in related cellular systems. K E Y W O R D Sinducible nitric oxide synthase, neutrophils, protein interaction, regulation, subcellular localization INTRODUCTIONSince its discovery as endothelium-derived growth factor, NO has been related to a broad spectrum of signaling pathways in diverse pathophysiological, immunomodulatory, 1-3 and pharmacological responses.NO regulates functional attributes of neutrophils modulating their chemotactic, phagocytic, migratory, and apoptotic activities 4 as elaborated in Fig. 1. Neutrophils generate NO at a rate of (10-100) nmoles /5 min/10 6 cells. 5 These comprise 60-70% of the total peripheral leukocytes in humans, contribute significantly to the circulating levels, encompassing a widespread impact on cardiovascular homeostasis.Being capable against invading pathogens, a tumor cell, and alloantigens, NO is an asset to these immunocompetent cells, adding more to their cytotoxic battalion. It has also been demonstrated that NO mediates neutrophil extracellular traps (NET) release at the site of Abbreviations: AL, arginosuccinate lyase; AS, arginosuccinate synthase; Asc, ascorbate; BH 4 , tetrahydrobioptein; CaM, calmodulim; CGD, chronic granulomatous disease; DHA, dehydroascorbate; ETC, electron transport chain; Hsp, heat shock protein; I B, inhibitor kappa B; NLS, nuclear localization signal; PDZ, PSD-95/Disc large/ZO-1; PKC, protein kinase C; RNI, reactive nitrogen intermediates; ROCK, Rho-associated coiled coil containing protein kinase; TGF, tumor growth factor inflammation / infection by augmenting free radical generation. 6 Study by Napimoga et al. 7 depicted that peroxisome proliferator-activated receptor-(PPAR-) reduces neutrophil migration to the acute inflammatory mesenteric lesion as a result of reduction of rolling and adhesion activities of neu...

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Regulation of inducible nitric oxide synthase by aggresome formation

Cited by 74 publications

References 30 publications

The physiologic aggresome mediates cellular inactivation of iNOS

The physiologic aggresome mediates cellular inactivation of iNOS

Redox Regulation of Protein Misfolding, Synaptic Damage, and Neuronal Loss in Neurodegenerative Diseases

Inducible nitric oxide synthase: An asset to neutrophils

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