IKKα controls ATG16L1 degradation to prevent ER stress during inflammation.
IKKα controls ATG16L1 degradation to prevent ER stress during inflammation.
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DOI：
10.1084/jem.20161867
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
Greten FR
中科院分区：
文献类型：
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作者：
Diamanti MA;Gupta J;Bennecke M;De Oliveira T;Ramakrishnan M;Braczynski AK;Richter B;Beli P;Hu Y;Saleh M;Mittelbronn M;Dikic I;Greten FR
降低的ATG 16 L1稳定性与发展炎症性肠病的易感性增加相关。Diamanti等人将IKKα鉴定为ATG 16 L1的中心上游激酶，提供了ATG 16 L1稳定性受TNF下游磷酸化和NOD活化控制的证据。抑制IκB激酶复合物（IKK）已涉及包括炎性肠病在内的几种慢性炎性疾病的治疗。在这项研究中，我们使用了一种失活的IKKα激酶（IkkαAA/AA）的小鼠，在急性结肠炎模型中，我们发现IKKα功能的丧失显著损害了上皮再生。从机制上讲，这是由IKKα突变型肠上皮细胞分泌细胞保护性IL-18受损引起的，因为在增强的未折叠蛋白应答（UPR）期间caspase 12活化升高。UPR的诱导与IkkαAA/AA小鼠中ATG 16 L1稳定性降低相关。我们证明了TNF-R和核苷酸结合寡聚化结构域刺激通过IKKα依赖性ATG 16 L1丝氨酸278位磷酸化促进ATG 16 L1稳定。因此，我们建议IKKα作为一个中央调解人感应细胞因子和微生物的刺激，以抑制内质网应激，从而确保在急性肠道炎症的功能。
Decreased ATG16L1 stabilization is associated with increased susceptibility to develop inflammatory bowel diseases. Diamanti et al. identify IKKα as a central upstream kinase of ATG16L1, providing evidence that ATG16L1 stabilization is controlled by phosphorylation downstream of TNF and NOD activation. Inhibition of the IκB kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKKα kinase (IkkαAA/AA), we show that loss of IKKα function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKKα-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR). Induction of the UPR is linked to decreased ATG16L1 stabilization in IkkαAA/AA mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKKα-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKKα as a central mediator sensing both cytokine and microbial stimulation to suppress endoplasmic reticulum stress, thereby assuring antiinflammatory function during acute intestinal inflammation.