The endoplasmic reticulum stress-mediated unfolded protein response protects against infection of goat endometrial epithelial cells by Trueperella pyogenes via autophagy.
The endoplasmic reticulum stress-mediated unfolded protein response protects against infection of goat endometrial epithelial cells by Trueperella pyogenes via autophagy.
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内质网应激介导的未折叠蛋白反应可保护山羊子宫内膜上皮细胞免受化脓性Trueperella通过自噬的感染
DOI：
10.1080/21505594.2021.2021630
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发表时间：
2022-12
期刊：
影响因子：
5.2
通讯作者：
中科院分区：
文献类型：
--
作者：
化脓性true eperella pypygenes是广泛存在于家畜和野生动物中的重要致病菌。自噬在消除化脓性梭菌过程中起着关键作用，这一过程依赖于雷帕霉素的机制靶点（mTOR）。内质网（ER）应激反应对自噬调节也至关重要。然而，内质网应激与化脓性芽孢杆菌之间的关系尚不清楚，化脓性芽孢杆菌的细胞内存活机制也没有得到充分的研究。在这项研究中，我们发现化脓性脓毒杆菌侵袭山羊子宫内膜上皮细胞（gEECs）。同时，我们观察到GRP78显著上调，未折叠蛋白反应（UPR）也在感染后被激活。此外，内质网应激激活剂和抑制剂分别下调和上调化脓性芽孢杆菌的细胞内存活。阻断UPR通路的三个臂分别不同程度地提高了化脓性t细胞的存活和炎症反应。我们还发现lc3标记的自噬体在入侵的化脓性t细胞周围形成，并且通过透射电镜在geec中可以看到自噬体样囊泡。此外，在自噬被阻断的情况下，tunicamycin并未抑制化脓性芽胞杆菌的细胞内存活。最后，化脓性梭菌的严重侵袭诱导宿主细胞凋亡，这也可能表明内质网应激在感染反应中的作用。综上所述，我们在这里证明内质网应激和UPR是抑制gEECs中化脓性t细胞内存活的自噬的新调节剂，有可能成为化脓性t细胞感染性疾病的有效治疗靶点。
Trueperella pyogenes is an important bacterial pathogen of a wide range of domestic and wild animals. Autophagy plays a key role in eliminating T. pyogenes in a process that is dependent on mechanistic target of rapamycin (mTOR). The endoplasmic reticulum (ER) stress response also is critical for autophagy regulation. However, the relationship between ER stress and T. pyogenes is uncharacterized and the intracellular survival mechanisms of T. pyogenes have not been investigated adequately. In this study, we show that T. pyogenes invades goat endometrial epithelial cells (gEECs). Meanwhile, we observed that GRP78 was upregulated significantly, and that unfolded protein response (UPR) also were activated after infection. Additionally, treatment with activators and inhibitors of ER stress downregulated and upregulated, respectively, intracellular survival of T. pyogenes. Blocking the three arms of the UPR pathway separately enhanced T. pyogenes survival and inflammatory reaction to different levels. We also show that LC3-labeled autophagosomes formed around the invading T. pyogenes and that autolysosome-like vesicles were visible in gEECs using transmission electron microscopy. Moreover, tunicamycin did not inhibit the intracellular survival of T. pyogenes under conditions in which autophagy was blocked. Finally, severe challenge with T. pyogenes induced host cell apoptosis which also may indicate a role for ER stress in the infection response. In summary, we demonstrate here that ER stress and UPR are novel modulators of autophagy that inhibit T. pyogenes intracellular survival in gEECs, which has the potential to be developed as an effective therapeutic target in T. pyogenes infectious disease.
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