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Blockade of endoplasmic reticulum stress-induced cell death by Ureaplasma parvum vacuolating factor
Cellular Microbiology ( IF 2.6 ) Pub Date : 2021-09-07 , DOI: 10.1111/cmi.13392 Fumiko Nishiumi 1 , Yasuhiro Kawai 1, 2 , Yukiko Nakura 1 , Michinobu Yoshimura 1, 3 , Heng Ning Wu 1 , Mitsuhide Hamaguchi 4, 5 , Shigeyuki Kakizawa 6 , Yo Suzuki 7 , John I Glass 7 , Itaru Yanagihara 1
Cellular Microbiology ( IF 2.6 ) Pub Date : 2021-09-07 , DOI: 10.1111/cmi.13392 Fumiko Nishiumi 1 , Yasuhiro Kawai 1, 2 , Yukiko Nakura 1 , Michinobu Yoshimura 1, 3 , Heng Ning Wu 1 , Mitsuhide Hamaguchi 4, 5 , Shigeyuki Kakizawa 6 , Yo Suzuki 7 , John I Glass 7 , Itaru Yanagihara 1
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Previously, we found that Ureaplasma parvum internalised into HeLa cells and cytosolic accumulation of galectin-3. U. parvum induced the host cellular membrane damage and survived there. Here, we conducted vesicular trafficking inhibitory screening in yeast to identify U. parvum vacuolating factor (UpVF). U. parvum triggered endoplasmic reticulum (ER) stress and upregulated the unfolded protein response-related factors, including BiP, P-eIF2 and IRE1 in the host cells, but it blocked the induction of the downstream apoptotic factors. MicroRNA library screening of U. parvum-infected cells and UpVF-transfected cells identified miR-211 and miR-214 as the negative regulators of the apoptotic cascade under ER stress. Transient expression of UpVF induced HeLa cell death with intracellular vacuolization; however, some stable UpVF transformant survived. U. parvum-infected cervical cell lines showed resistance to actinomycin D, and UpVF stable transformant cell lines exhibited resistance to X-ray irradiation, as well as cisplatin and paclitaxel. UpVF expressing cervical cancer xenografts in nude mice also acquired resistance to cisplatin and paclitaxel. A mycoplasma expression vector based on Mycoplasma mycoides, Syn-MBA (multiple banded antigen)-UpVF, reduced HeLa cell survival compared with that of Syn-MBA after 72 hr of infection. These findings together suggest novel mechanisms for Ureaplasma infection and the possible implications for cervical cancer malignancy.
中文翻译：
小脲原体空泡化因子阻断内质网应激诱导的细胞死亡
以前，我们发现Ureaplasma parvum内化到 HeLa 细胞和 galectin-3 的细胞溶质积累。U. parvum诱导宿主细胞膜损伤并在那里存活。在这里，我们在酵母中进行了囊泡运输抑制筛选，以鉴定U. parvum空泡化因子 (UpVF)。U. parvum引发内质网 (ER) 应激并上调宿主细胞中未折叠蛋白反应相关因子，包括 BiP、P-eIF2 和 IRE1，但它阻断了下游凋亡因子的诱导。U. parvum的 MicroRNA 文库筛选感染细胞和转染 UpVF 的细胞将 miR-211 和 miR-214 鉴定为 ER 应激下凋亡级联的负调节因子。UpVF的瞬时表达诱导HeLa细胞死亡并伴有细胞内空泡化；然而，一些稳定的 UpVF 转化体存活了下来。U. parvum感染的宫颈细胞系表现出对放线菌素 D 的抗性，UpVF 稳定的转化细胞系表现出对 X 射线照射以及顺铂和紫杉醇的抗性。在裸鼠中表达 UpVF 的宫颈癌异种移植物也获得了对顺铂和紫杉醇的耐药性。一种基于蕈状支原体的支原体表达载体，与 Syn-MBA 相比，Syn-MBA（多带抗原）-UpVF 在感染 72 小时后降低了 HeLa 细胞的存活率。这些发现共同表明了脲原体感染的新机制以及对宫颈癌恶性肿瘤的可能影响。
更新日期：2021-09-07
中文翻译：
小脲原体空泡化因子阻断内质网应激诱导的细胞死亡
以前，我们发现Ureaplasma parvum内化到 HeLa 细胞和 galectin-3 的细胞溶质积累。U. parvum诱导宿主细胞膜损伤并在那里存活。在这里，我们在酵母中进行了囊泡运输抑制筛选，以鉴定U. parvum空泡化因子 (UpVF)。U. parvum引发内质网 (ER) 应激并上调宿主细胞中未折叠蛋白反应相关因子，包括 BiP、P-eIF2 和 IRE1，但它阻断了下游凋亡因子的诱导。U. parvum的 MicroRNA 文库筛选感染细胞和转染 UpVF 的细胞将 miR-211 和 miR-214 鉴定为 ER 应激下凋亡级联的负调节因子。UpVF的瞬时表达诱导HeLa细胞死亡并伴有细胞内空泡化；然而，一些稳定的 UpVF 转化体存活了下来。U. parvum感染的宫颈细胞系表现出对放线菌素 D 的抗性，UpVF 稳定的转化细胞系表现出对 X 射线照射以及顺铂和紫杉醇的抗性。在裸鼠中表达 UpVF 的宫颈癌异种移植物也获得了对顺铂和紫杉醇的耐药性。一种基于蕈状支原体的支原体表达载体，与 Syn-MBA 相比，Syn-MBA（多带抗原）-UpVF 在感染 72 小时后降低了 HeLa 细胞的存活率。这些发现共同表明了脲原体感染的新机制以及对宫颈癌恶性肿瘤的可能影响。
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