HIF1A regulates xenophagic degradation of adherent and invasive Escherichia coli (AIEC).
HIF1A regulates xenophagic degradation of adherent and invasive Escherichia coli (AIEC).
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DOI：
10.4161/15548627.2014.984275
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发表时间：
2014
期刊：
影响因子：
13.3
通讯作者：
Vouret-Craviari V
中科院分区：
文献类型：
--
作者：
Mimouna S;Bazin M;Mograbi B;Darfeuille-Michaud A;Brest P;Hofman P;Vouret-Craviari V
低氧诱导转录因子HIF1激活自噬，这是一种参与维持细胞内稳态的一般分解代谢途径。自噬和HIF1的功能障碍与越来越多的人类疾病有关，包括炎症性肠病(IBD)，如克罗恩病(CD)。黏附性侵袭性大肠杆菌(AIEC)通过激活HIF依赖的反应，定植于CD患者的回肠黏膜，强烈促进胃肠炎性疾病。在这里，我们的目标是表征HIF1在异种吞噬中的作用，异种吞噬是一种特殊的自噬形式，涉及细胞内细菌的降解。我们的结果表明，内源性HIF1a基因敲除增加了AIEC在肠上皮细胞中的存活。我们证明，存活率的增加与自溶酶体成熟阶段自噬通量的显著损害有关。此外，我们发现AIEC仍然存在于单膜Lc3-II阳性囊泡中，并且它们不能诱导ULK1的磷酸化。这些结果表明，在缺乏HIF1a的情况下，在与Lc3相关的吞噬体内发现了AIEC。利用针对TLR5和CEACAM6这两个已知的AIEC结合受体的阻断抗体，我们证明下游受体信号是介导ULK1磷酸化所必需的。最后，我们提供了证据，证明HIF1介导CEACAM6的表达，并且CEACAM6是在含有细菌的信号中心招募ULK1所必需的。总之，这些结果确定了HIF1在AIEC特异性异种吞噬中的新功能，并提示自噬和HIF1a表达的共同激活可能是解决CD患者AIEC感染的一种潜在的新疗法。
The hypoxia inducible transcription factor HIF1 activates autophagy, a general catabolic pathway involved in the maintenance of cellular homeostasis. Dysfunction in both autophagy and HIF1 has been implicated in an increasing number of human diseases, including inflammatory bowel disease (IBD), such as Crohn disease (CD). Adherent invasive E. coli (AIEC) colonize ileal mucosa of CD patients and strongly promote gastrointestinal inflammatory disorders by activation of HIF-dependent responses. Here, we aim to characterize the contribution of HIF1 in xenophagy, a specialized form of autophagy involved in the degradation of intracellular bacteria. Our results showed that endogenous HIF1A knockdown increased AIEC survival in intestinal epithelial cells. We demonstrate that the increase in survival rate correlates with a dramatic impairment of the autophagic flux at the autolysosomal maturation step. Furthermore, we show that AIEC remained within single-membrane LC3-II-positive vesicles and that they were unable to induce the phosphorylation of ULK1. These results suggested that, in the absence of HIF1A, AIEC were found within LC3-associated phagosomes. Using blocking antibodies against TLR5 and CEACAM6, the 2 well-known AIEC-bound receptors, we showed that downstream receptor signaling was necessary to mediate ULK1 phosphorylation. Finally, we provide evidence that HIF1 mediates CEACAM6 expression and that CEACAM6 is necessary to recruit ULK1 in a bacteria-containing signaling hub. Collectively, these results identify a new function for HIF1 in AIEC-dedicated xenophagy, and suggest that coactivation of autophagy and HIF1A expression may be a potential new therapy to resolve AIEC infection in CD patients.