Ambient Light Promotes Selective Subcellular Proteotoxicity after Endogenous and Exogenous Porphyrinogenic Stress

Maitra, Dhiman; Elenbaas, Jared S.; Whitesall, Steven E.; Basrur, Venkatesha; DʼAlecy, Louis G.; Omary, M. Bishr

doi:10.1074/jbc.m114.636001

Cited by 28 publications

(83 citation statements)

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“…Porphyrins are known to cause oxidative stress in the absence of light (21,22,24,61), but concomitant porphyrinmediated protein aggregation in mice and cell culture systems has not been reported until recently (15,35). The effects of protein aggregation are not well known in the context of porphyria-induced tissue damage.…”

Section: Discussionmentioning

confidence: 99%

“…It is noteworthy that the expression of eGFP in A19 larvae is liver specific (34). Transgenic FECH (3–5 mo old) and DDC‐fed (5 d, 0.1% DDC) mice were used as described previously (15, 35). Animal care guidelines were followed as approved by the University of Michigan Animal Care and Use Committee and per recommendations in the Guide for the Care and Use of Laboratory Animals from the National Institutes of Health (Bethesda, MD, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Gel strips were digested with trypsin, then analyzed by MS. Aggregated proteins were defined as the polypeptides that were detected >150 kDa but have a known monomeric molecular mass of < 125 kDa, and were found in the treated but not the control samples. Porphyrin quantification was described previously (35).…”

Section: Methodsmentioning

confidence: 99%

“…All fish experiments were conducted using wild-type zebrafish (Danio rerio) larvae from a cross of AB and TL adult zebrafish (ABTL) or transgenic ABTL zebrafish with eukaryotic green fluorescent protein (eGFP)-tagged fibrinogen b [A19 line (34)]. It is noteworthy that the expression of eGFP in A19 larvae is liver specific (34).TransgenicFECH (3-5 mo old) and DDC-fed (5 d, 0.1% DDC) mice were used as described previously (15,35). Animal care guidelines were followed as approved by the University of Michigan Animal Care and Use Committee and per recommendations in the Guide for the Care and Use of Laboratory Animals from the National Institutes of Health (Bethesda, MD, USA).…”

Section: Fish Lines and Husbandry And Micementioning

confidence: 99%

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A precursor‐inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress

et al. 2016

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Protoporphyria is a metabolic disease that causes excess production of protoporphyrin IX (PP-IX), the final biosynthetic precursor to heme. Hepatic PP-IX accumulation may lead to end-stage liver disease. We tested the hypothesis that systemic administration of porphyrin precursors to zebrafish larvae results in protoporphyrin accumulation and a reproducible nongenetic porphyria model. Retro-orbital infusion of PP-IX or the iron chelator deferoxamine mesylate (DFO), with the first committed heme precursor α-aminolevulinic acid (ALA), generates high levels of PP-IX in zebrafish larvae. Exogenously infused or endogenously produced PP-IX accumulates preferentially in the liver of zebrafish larvae and peaks 1 to 3 d after infusion. Similar to patients with protoporphyria, PP-IX is excreted through the biliary system. Porphyrin accumulation in zebrafish liver causes multiorganelle protein aggregation as determined by mass spectrometry and immunoblotting. Endoplasmic reticulum stress and induction of autophagy were noted in zebrafish larvae and corroborated in 2 mouse models of protoporphyria. Furthermore, electron microscopy of zebrafish livers from larvae administered ALA + DFO showed hepatocyte autophagosomes, nuclear membrane ruffling, and porphyrin-containing vacuoles with endoplasmic reticulum distortion. In conclusion, systemic administration of the heme precursors PP-IX or ALA + DFO into zebrafish larvae provides a new model of acute protoporphyria with consequent hepatocyte protein aggregation and proteotoxic multiorganelle alterations and stress.-Elenbaas, J. S., Maitra, D., Liu, Y., Lentz, S. I., Nelson, B., Hoenerhoff, M. J., Shavit, J. A., Omary, M. B. A precursor-inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Fish Lines and Husbandry And Micementioning

confidence: 99%

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A precursor‐inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress

et al. 2016

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“…These findings thus excluded both UPD and ALD involvement in this IκBα-loss. Further 161 supportive evidence was provided by studies in HepG2 cells transfected with a S 32 A/S 36 results in PPIX-accumulation, we examined whether this accumulation (and not heme 180 deficiency) was mainly responsible for the observed IκBα loss and NF-κB activation. We 181 observed a greater IκBα loss after either PPIX or ZnPP relative to that seen with NMPP alone 182 ( Fig.…”

Section: Nmpp-elicited Ppix Accumulation With Concurrent Iκbα-loss Anmentioning

confidence: 81%

A Novel Mechanism for NF-κB-Activation via IκB-Aggregation: Implications for Hepatic Mallory-denk-body Induced Inflammation

Liu¹,

Trnka²,

Guan³

et al. 2019

Preprint

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Background & AimsMallory-Denk-bodies (MDBs) are hepatic protein aggregates associated with inflammation both clinically and in MDB-inducing models. Similar protein aggregation in neurodegenerative diseases also triggers inflammation and NF-κB activation. However, the precise mechanism that links protein aggregation to NFκB-activation and inflammatory response remains unclear.MethodsHerein, we find that treating primary hepatocytes with MDB-inducing agents (N-methylprotoporphyrin, protoporphyrin IX (PPIX), or ZnPPIX) elicited an IκBα-loss with consequent NF-κB activation. We characterized the underlying mechanism in detail using hepatocytes from various knockout mice and MEF cell lines and multiple approaches including immunoblotting, EMSA, RT-PCR, confocal immunofluorescence microscopy, affinity immunoprecipitation, and protein solubility assays. Additionally, we performed rigorous proteomic analyses to identify the proteins aggregating upon PPIX treatment and/or co-aggregating with IκBα.ResultsFour known mechanisms of IκBα-loss were probed and excluded. Immunofluorescence analyses of ZnPPIX-treated cells coupled with 8 M urea/CHAPS-extraction revealed that this IκBα-loss was due to its sequestration along with IκBβ into insoluble aggregates. Through proteomic analyses we identified 47 aggregation-prone proteins that co-aggregate with IκBα through direct interaction or proximity. Of these ZnPPIX-aggregation targets, the nucleoporins Nup153 and Nup358/RanBP2 were identified through RNA-interference, as likely mediators of IκBα-nuclear import.ConclusionWe discovered a novel mechanism of inflammatory NF-κB activation through IκB-sequestration into insoluble aggregates along with interacting aggregation-prone proteins. This mechanism may account for the protein aggregate-induced inflammation observed in MDB-associated liver diseases, thereby identifying novel targets for therapeutic intervention. Because of inherent commonalities this MDB cell model is a bona fide protoporphyric model, making these findings equally relevant to the liver inflammation associated with clinical protoporphyria.Lay SummaryMallory-Denk-bodies (MDBs) are hepatic protein aggregates commonly featured in many liver diseases. MDB-presence is associated with the induction of inflammatory responses both clinically and in all MDB-inducing models. Similar protein aggregation in neurodegenerative diseases is also known to trigger inflammation and NFκB pathway activation via an as yet to be characterized non-canonical mechanism. Herein using a MDB-inducing cell model, we uncovered a novel mechanism for NFκB activation via cytosolic IκB-sequestration into insoluble aggregates. Furthermore, using a proteomic approach, we identified 47 aggregation-prone proteins that interact and co-aggregate with IκBα. This novel mechanism may account for the protein aggregate-induced inflammation observed in liver diseases, thereby identifying novel targets for therapeutic intervention.

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Multifunctional Photonic Nanomaterials for Diagnostic, Therapeutic, and Theranostic Applications

Kim¹,

et al. 2018

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The last decade has seen dramatic progress in the principle, design, and fabrication of photonic nanomaterials with various optical properties and functionalities. Light-emitting and light-responsive nanomaterials, such as semiconductor quantum dots, plasmonic metal nanoparticles, organic carbon, and polymeric nanomaterials, offer promising approaches to low-cost and effective diagnostic, therapeutic, and theranostic applications. Reasonable endeavors have begun to translate some of the promising photonic nanomaterials to the clinic. Here, current research on the state-of-the-art and emerging photonic nanomaterials for diverse biomedical applications is reviewed, and the remaining challenges and future perspectives are discussed.

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Ambient Light Promotes Selective Subcellular Proteotoxicity after Endogenous and Exogenous Porphyrinogenic Stress

Cited by 28 publications

References 32 publications

A precursor‐inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress

A precursor‐inducible zebrafish model of acute protoporphyria with hepatic protein aggregation and multiorganelle stress

A Novel Mechanism for NF-κB-Activation via IκB-Aggregation: Implications for Hepatic Mallory-denk-body Induced Inflammation

Multifunctional Photonic Nanomaterials for Diagnostic, Therapeutic, and Theranostic Applications

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