Gadd45α activity is the principal effector of Shigella mitochondria-dependent epithelial cell death in vitro and ex vivo

Fazio, Luigi Lembo; Nigro, Giulia; Noël, Gaëlle; Rossi, Giacomo; Chiara, Federica; Tsilingiri, Katerina; Rescigno, María; Rasola, Andrea; Bernardini, Maria Lina

doi:10.1038/cddis.2011.4

Cited by 21 publications

(19 citation statements)

References 40 publications

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“…Indeed, bacteria do not proliferate within these cell populations, and they likely survive for a while. Shigella-infected epithelial cells also activate death programs (27,48,49). However, at the same time, these cells initiate a prosurvival response (27,50) allowing the bacteria to multiply and to colonize the microenvironment up until the death of the cells (51).…”

Section: Discussionmentioning

confidence: 99%

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IntracellularShigellaremodels its LPS to dampen the innate immune recognition and evade inflammasome activation

Paciello¹,

Silipo

Fazio³

et al. 2013

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

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Section: Discussionmentioning

confidence: 99%

“…Total protein extracts obtained through cell lysis and Western blot procedures were carried out as described (27). Protein extraction from cell culture supernatants was performed as reported (70).…”

Section: Recovery Of Lps From Intracellular Bacteria and Preparation mentioning

confidence: 99%

IntracellularShigellaremodels its LPS to dampen the innate immune recognition and evade inflammasome activation

Paciello¹,

Silipo

Fazio³

et al. 2013

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

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“…1F, S1B). S. flexneri infection is known to induce apoptosis in epithelial cells (Carneiro, Travassos et al, 2009, Lembo-Fazio, Nigro et al, 2011. However, the kinetic of activation of caspase-3 upon bacterial infection was not different between EGFP-RIPK2 expressing cells and unmodified HeLa cells ( Fig.…”

Section: Ripk2 Forms Cytosolic Riposomes Upon Bacterial Infectionmentioning

confidence: 90%

XIAP controls RIPK2 signaling by preventing its deposition in speck-like structures

Ellwanger

Arnold

Briese

et al. 2019

Preprint

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The receptor interacting serine/threonine kinase 2 (RIPK2) is essential for linking activation of the pattern recognition receptors NOD1 and NOD2 to cellular signaling events.Recently, it was shown that RIPK2 forms higher order molecular structures in vitro, which were proposed to activate signaling. Here, we demonstrate that RIPK2 forms detergent insoluble complexes in the cytosol of host cells upon infection with invasive enteropathogenic bacteria. Formation of these structures occurred after NF-κB activation and depends on the CARD of NOD1 or NOD2. Complex formation upon activation was dependent on RIPK2 autophosphorylation at Y474 and influenced by phosphorylation at S176. Inhibition of activity of the cIAP protein XIAP induced spontaneous complex formation of RIPK2 but blocked NOD1-dependet NF-κB activation. Using immunoprecipitation, we identified 14-3-3 proteins as novel binding partners of non-activated RIPK2, whereas complexed RIPK2 was bound by the prohibitin proteins Erlin-1 and Erlin-2.Taken together, our work reveals novel roles of XIAP, 14-3-3 and Erlin proteins in the regulation of RIPK2 and expands our knowledge on the function of RIPK2 posttranslational modifications in NOD1/2 signaling. AUTHOR CONTRIBUTIONSCA, KE, SB and IK performed the experiments.JP performed MS analysis and data processing.TAK conceived and supervised the study.CA, KE and TAK wrote and edited the manuscript. CONFLICT OF INTERESTThe authors declare that they have no conflict of interest.A: Indirect immunofluorescence micrographs of HeLa EGFP-RIPK2 cells infected for 2 h with S. flexneri M90T. Staining for XIAP, EGFP-RIPK2, and merge with DNA-staining is shown.Co-localization is shown at higher magnification in the inlay. Scale bar = 10 µm. B: Fluorescence micrographs of HeLa EGFP-RIPK2 cells, treated for 48 h with a XIAP siRNA or a non-targeting siRNA, following infection with S. flexneri M90T for 2 h or left uninfected. Cells were treated with 1 µg/ml doxycycline for 24 h prior infection. EGFP-RIPK2 and merge with DNA-staining is shown. Scale bar = 10 µm. C: IL-8 release in the supernatants from HeLa EGFP-RIPK2 cells, treated for 48 h with a XIAP siRNA or a non-targeting siRNA, following infection with S. flexneri M90T for 6 h. Mean of n=2 with S.D. is shown. D: Immunoblot analysis of HeLa EGFP-RIPK2 cells infected with S. flexneri M90T or BS176 for the indicated time. Immunoblot was probed with anti-RIPK2 antibody, anti-XIAP, and anti-β-tubulin as loading control. E: Left panel: Fluorescence micrographs of HeLa EGFP-RIPK2 cells, transfected with 500 ng Ubi-SMAC-fl-pDS-RED, Ubi-SMAC-tr-pDS-RED, or Ubi-SMAC-AVPI-pDS-RED plasmid and treated with 1 µg/ml doxycycline for 24 h. EGFP-RIPK2, SMAC-dsRed, and merge with DNA-staining is shown. Scale bar = 10 µm. Right panel: Immunoblot analysis of cells prepared as in the left panel. Protein levels were detected using an anti-RIPK2 antibody and anti-β-tubulin as loading control.Figure 6: Phosphorylation of RIPK2 at S176 and Y474 contribute to RIPosome formation. A: Fluorescence microg...

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“…The knockdown of APE1 by siRNA increased the proliferation capacity of WI38 cells and also reduced the mRNA expression of senescence-related genes (e.g., p16, p21) ( Fig EV5F and G). Furthermore, colon samples from old people showed significantly higher percentage of GADD45A and c-H2AX-positive cells as compared to young ones ( Fig 6E-G and Appendix Table S1), and the upregulation of GADD45A is related to inflammation in human colon [39]. These data indicate that GADD45A and BER pathways participate in the replicative aging of human cells.…”

Section: Gadd45a Knockdown or Ape1 Inhibition Delays Replicative Senementioning

confidence: 74%

Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan

Diao

Wang

et al. 2018

EMBO Reports

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Progressive attrition of telomeres triggers DNA damage response (DDR) and limits the regenerative capacity of adult stem cells during mammalian aging. Intriguingly, telomere integrity is not only determined by telomere length but also by the epigenetic status of telomeric/sub-telomeric regions. However, the functional interplay between DDR induced by telomere shortening and epigenetic modifications in aging remains unclear. Here, we show that deletion of Gadd45a improves the maintenance and function of intestinal stem cells (ISCs) and prolongs lifespan of telomerase-deficient mice (G3 ). Mechanistically, Gadd45a facilitates the generation of a permissive chromatin state for DDR signaling by inducing base excision repair-dependent demethylation of CpG islands specifically at sub-telomeric regions of short telomeres. Deletion of Gadd45a promotes chromatin compaction in sub-telomeric regions and attenuates DDR initiation at short telomeres of G3 ISCs. Treatment with a small molecule inhibitor of base excision repair reduces DDR and improves the maintenance and function of G3 ISCs. Taken together, our study proposes a therapeutic approach to enhance stem cell function and prolong lifespan by targeting epigenetic modifiers.

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Gadd45α activity is the principal effector of Shigella mitochondria-dependent epithelial cell death in vitro and ex vivo

Cited by 21 publications

References 40 publications

IntracellularShigellaremodels its LPS to dampen the innate immune recognition and evade inflammasome activation

IntracellularShigellaremodels its LPS to dampen the innate immune recognition and evade inflammasome activation

XIAP controls RIPK2 signaling by preventing its deposition in speck-like structures

Telomeric epigenetic response mediated by Gadd45a regulates stem cell aging and lifespan

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