Molecular mechanisms of Streptococcus pneumoniae-targeted autophagy via pneumolysin, Golgi-resident Rab41, and Nedd4-1-mediated K63-linked ubiquitination
Molecular mechanisms of Streptococcus pneumoniae-targeted autophagy via pneumolysin, Golgi-resident Rab41, and Nedd4-1-mediated K63-linked ubiquitination
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DOI：
10.1111/cmi.12846
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发表时间：
2018-08-01
影响因子：
3.4
通讯作者：
Ohnishi, Makoto
中科院分区：
文献类型：
--
作者：
Ogawa, Michinaga;Matsuda, Ryuta;Ohnishi, Makoto
肺炎链球菌是社区获得性肺炎最常见的病原体，可穿透上皮屏障进入血液和大脑。我们研究了肺炎链球菌的胞内命运，发现该病原体是通过肺炎溶血素和泛素-p62-LC3货物依赖的选择性自噬方式被捕获的。重要的是，在诱导自噬后，Rab41被从高尔基体重新定位到含有肺炎链球菌的自噬小泡(PcAV)上，这些囊泡只有在Rab41阳性的完整高尔基体存在时才形成。此外，随后K48和K63连接的多泛素链在PcAV中和在PcAV上的定位和调节是明显不同的。最后，我们发现E3连接酶Nedd4-1被募集到PcAV上，并在PcAV上K63连接的多泛素链(K63Ub)的产生、促进PcAV的形成和消除细胞内肺炎链球菌中发挥关键作用。这些发现表明，Nedd4-1介导的K63Ub在PcAV上的沉积是PcAV生物发生和有效消除宿主细胞侵袭的肺炎球菌的支架。
Streptococcus pneumoniae is the most common causative agent of community-acquired pneumonia and can penetrate epithelial barriers to enter the bloodstream and brain. We investigated intracellular fates of S.pneumoniae and found that the pathogen is entrapped by selective autophagy in pneumolysin- and ubiquitin-p62-LC3 cargo-dependent manners. Importantly, following induction of autophagy, Rab41 was relocated from the Golgi apparatus to S.pneumoniae-containing autophagic vesicles (PcAV), which were only formed in the presence of Rab41-positive intact Golgi apparatuses. Moreover, subsequent localization and regulation of K48- and K63-linked polyubiquitin chains in and on PcAV were clearly distinguishable from each other. Finally, we found that E3 ligase Nedd4-1 was recruited to PcAV and played a pivotal role in K63-linked polyubiquitin chain (K63Ub) generation on PcAV, promotion of PcAV formation, and elimination of intracellular S.pneumoniae. These findings suggest that Nedd4-1-mediated K63Ub deposition on PcAV acts as a scaffold for PcAV biogenesis and efficient elimination of host cell-invaded pneumococci.