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ATG16L1 down-regulates IL-1beta signaling via neddylated- Cullin-3 mediated p62 ubiquitination

Abstract

The Genome-Wide Association Studies shows that ATG16L1 mutation such as single-mutation polymorphism or miss sense mutation makes a person susceptible to Crohn's Disease, a type of inflammatory bowel diseases. Then, we examined how the loss of ATG16L1 functions effects signal transduction pathways with present of pro-inflammatory stimulus. Using in vitro experiment with mouse embryonic fibroblast (MEF) cell-line, we have checked that deletion of ATG16L1 will significantly influence the amplification of IL-1[beta] signaling. Then, we have expected that influence of ATG16L1 occurs in the upstream of IL-1[beta] signaling cascade, and our result presents that increased p62 expression in ATG16L1 knockout cells result in stronger inflammatory response due to oligomerization of TRAF6. Also the data shows that ATG16L1 is required for ubiquitination and degradation of p62 and that ATG16L1 is the essential component to neddylate Cullin-3 (Cul-3), E3 ubiquitin ligase, to bring ubiquitin to p62. These findings implicate that ATG16L1 is important factor to suppress IL-1[beta] signaling through down-regulation of p62 level by Cul-3 neddylation. Importantly, future study may provide therapeutic solutions to pathological conditions due to increased p62 expression level. Also, this study might give a direction for treatment in Crohn's Disease patients with susceptible allele of ATG16L1 by specifically targeting Cullin-3 and p62

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