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Crosstalk between JNK and SUMO signaling pathways: deSUMOylation is protective against H2O2-induced cell injury.

ABSTRACT: Oxidative stress is a key feature in the pathogenesis of several neurological disorders. Following oxidative stress stimuli a wide range of pathways are activated and contribute to cellular death. The mechanism that couples c-Jun N-terminal kinase (JNK) signaling, a key pathway in stress conditions, to the small ubiquitin-related modifier (SUMO), an emerging protein in the field, is largely unknown.With this study we investigated if SUMOylation participates in the regulation of JNK activation as well as cellular death in a model of H(2)O(2) induced-oxidative stress. Our data show that H(2)O(2) modulates JNK activation and induces cellular death in neuroblastoma SH-SY5Y cells. Inhibition of JNK's action with the D-JNKI1 peptide rescued cells from death. Following H(2)O(2), SUMO-1 over-expression increased phosphorylation of JNK and exacerbated cell death, although only in conditions of mild oxidative stress. Furthermore inhibition of SUMOylation, following transfection with SENP1, interfered with JNK activation and rescued cells from H(2)O(2) induced death. Importantly, in our model, direct interaction between these proteins can occur.Taken together our results show that SUMOylation may significantly contribute to modulation of JNK activation and contribute to cell death in oxidative stress conditions.

SUBMITTER: Feligioni M

PROVIDER: S-EPMC3229511 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Crosstalk between JNK and SUMO signaling pathways: deSUMOylation is protective against H2O2-induced cell injury.

Feligioni Marco M Brambilla Elisa E Camassa Agata A Sclip Alessandra A Arnaboldi Andrea A Morelli Federica F Antoniou Xanthi X Borsello Tiziana T

PloS one 20111202 12

<h4>Background</h4>Oxidative stress is a key feature in the pathogenesis of several neurological disorders. Following oxidative stress stimuli a wide range of pathways are activated and contribute to cellular death. The mechanism that couples c-Jun N-terminal kinase (JNK) signaling, a key pathway in stress conditions, to the small ubiquitin-related modifier (SUMO), an emerging protein in the field, is largely unknown.<h4>Methodology/principal findings</h4>With this study we investigated if SUMOy ...[more]

PMID: 22164242

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Project description:Background & aimsHeat shock protein (Hsp) 72 is a molecular chaperone that has broad cytoprotective functions and is upregulated in response to stress. To determine its hepatic functions, we studied its expression in human liver disorders and its biological significance in newly generated transgenic animals.MethodsDouble transgenic mice overexpressing Hsp72 (gene Hspa1a) under the control of a tissue-specific tetracycline-inducible system (Hsp72-LAP mice) were produced. Acute liver injury was induced by a single injection of acetaminophen (APAP). Feeding with either a methionine choline-deficient (MCD; 8 weeks) or a 3,5-diethoxycarbonyl-1,4-dihydrocollidine-supplemented diet (DDC; 12 weeks) was used to induce lipotoxic injury and Mallory-Denk body (MDB) formation, respectively. Primary hepatocytes were treated with palmitic acid.ResultsPatients with non-alcoholic steatohepatitis and chronic hepatitis C infection displayed elevated HSP72 levels. These levels increased with the extent of hepatic inflammation and HSP72 expression was induced after treatment with either interleukin (IL)-1β or IL-6. Hsp72-LAP mice exhibited robust, hepatocyte-specific Hsp72 overexpression. Primary hepatocytes from these animals were more resistant to isolation-induced stress and Hsp72-LAP mice displayed lower levels of hepatic injury in vivo. Mice overexpressing Hsp72 had fewer APAP protein adducts and were protected from oxidative stress and APAP-/MCD-induced cell death. Hsp72-LAP mice and/or hepatocytes displayed significantly attenuated Jnk activation. Overexpression of Hsp72 did not affect steatosis or the extent of MDB formation.ConclusionsOur results demonstrate that HSP72 induction occurs in human liver disease, thus, HSP72 represents an attractive therapeutic target owing to its broad hepatoprotective functions.Lay summaryHSP72 constitutes a stress-inducible, protective protein. Our data demonstrate that it is upregulated in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Moreover, Hsp72-overexpressing mice are protected from various forms of liver stress.

Dataset Information

Crosstalk between JNK and SUMO signaling pathways: deSUMOylation is protective against H2O2-induced cell injury.

Publications

Crosstalk between JNK and SUMO signaling pathways: deSUMOylation is protective against H2O2-induced cell injury.

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