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| Item Type: | Preprint |
|---|---|
| Title: | Autophagy limits inflammatory gene expression through targeting of nuclear p65/RelA by LC3 and p62 for lysosomal degradation |
| Creators Name: | Brischetto, C., Mucka, P., Kaergel, E. and Scheidereit, C. |
| Abstract: | The interplay between NF-κB signaling and autophagy regulates inflammatory signaling in different cellular contexts and in response to different stimuli. The impairment of this crosstalk may play a role in chronic inflammation and in tumorigenesis. However, the molecular mechanism by which these two pathways interact to regulate the inflammatory response remains elusive. By using biochemical analysis and imaging techniques, we characterized the interaction of the endogenous autophagic marker LC3 and NF-κB/p65 in response to different stress conditions. Following irradiation or TNFα stimulation, nuclear accumulation of LC3 strongly co-localized with p65, suggesting that nuclear p65 is targeted for autophagic degradation. Mechanistically, we showed that the nuclear p65-LC3 interaction is mediated by ubiquitination of the same p65, which is recognized by the cargo receptor p62, resulting in its cytoplasmic export and lysosomal proteolysis. Accordingly, autophagy inhibition by depletion of the essential autophagy gene ATG16L1 selectively stabilizes nuclear p65, in turn enhancing NF-κB gene expression of pro-inflammatory cytokine. Our results revealed a novel molecular mechanism that modulates the NF-κB inflammatory response through nuclear sequestration of the NF-κB/p65 subunit by autophagy proteins. These findings are of importance for developing novel therapeutic strategies against chronic inflammatory diseases displaying defective autophagy and constitutive NF-κB activity. |
| Keywords: | Autophagy, Lysosome, Proteasome, Chronic Inflammation, NF-κB, Transcription, Degradation |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2022.11.02.514846 |
| Date: | 2 November 2022 |
| Official Publication: | https://doi.org/10.1101/2022.11.02.514846 |
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