Blockade of endoplasmic reticulum stress-induced cell death by Ureaplasma parvum vacuolating factor

IF 2.6 2区生物学 Q3 CELL BIOLOGY

Cellular Microbiology Pub Date : 2021-09-07 DOI:10.1111/cmi.13392

Fumiko Nishiumi, Yasuhiro Kawai, Yukiko Nakura, Michinobu Yoshimura, Heng Ning Wu, Mitsuhide Hamaguchi, Shigeyuki Kakizawa, Yo Suzuki, John I. Glass, Itaru Yanagihara

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引用次数: 10

Abstract

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.

Take Aways

• Ureaplasmal novel virulence factor, UpVF, was identified.

• UpVF triggered ER stress but suppressed apoptotic cascade via miR-211 and -214.

• UpVF conferred resistance to anticancer treatments both in vivo and in vitro.

• Dual expression of MBA and UpVF in JCVI-syn3B showed host cell damage.

Abstract Image

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细小脲原体空泡因子对内质网应激诱导细胞死亡的阻断作用

在此之前，我们发现细小脲原体内化到HeLa细胞中并在胞质中积累半凝集素-3。细小球菌诱导宿主细胞膜损伤并存活。在此，我们在酵母中进行了囊泡运输抑制筛选，以鉴定U. parvum空泡因子(UpVF)。U. parvum触发宿主细胞内质网应激，上调未折叠蛋白反应相关因子，包括BiP、P-eIF2和IRE1，但阻断下游凋亡因子的诱导。对感染U. parvum的细胞和转染upvf的细胞进行MicroRNA文库筛选，发现miR-211和miR-214是内质网应激下凋亡级联的负调节因子。瞬时表达UpVF诱导HeLa细胞空泡化死亡;然而，一些稳定的UpVF变换幸存下来。感染U. parvum的宫颈细胞系对放线菌素D有耐药性，UpVF稳定转化细胞系对x射线照射、顺铂和紫杉醇均有耐药性。在裸鼠中表达UpVF的宫颈癌异种移植物也获得了顺铂和紫杉醇的耐药性。一种基于支原体的支原体表达载体，Syn-MBA(多带状抗原)-UpVF，在感染72小时后，与Syn-MBA相比，HeLa细胞存活率降低。这些发现共同提示了尿原体感染的新机制和宫颈癌恶性肿瘤的可能意义。Take Aways•脲原体新型毒力因子UpVF被鉴定出来。•UpVF触发内质网应激，但通过miR-211和-214抑制凋亡级联。•UpVF在体内和体外均赋予抗癌治疗的抗性。•JCVI-syn3B中MBA和UpVF的双表达显示宿主细胞损伤。

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来源期刊

Cellular Microbiology 生物-微生物学

CiteScore

9.70

自引率

0.00%

发文量

审稿时长

3 months

期刊介绍： Cellular Microbiology aims to publish outstanding contributions to the understanding of interactions between microbes, prokaryotes and eukaryotes, and their host in the context of pathogenic or mutualistic relationships, including co-infections and microbiota. We welcome studies on single cells, animals and plants, and encourage the use of model hosts and organoid cultures. Submission on cell and molecular biological aspects of microbes, such as their intracellular organization or the establishment and maintenance of their architecture in relation to virulence and pathogenicity are also encouraged. Contributions must provide mechanistic insights supported by quantitative data obtained through imaging, cellular, biochemical, structural or genetic approaches.