Lu Shiou-Ling, Kawabata Tsuyoshi, Cheng Yi-Lin, Omori Hiroko, Hamasaki Maho, Kusaba Tatsuya, Iwamoto Ryo, Arimoto Hirokazu, Noda Takeshi, Lin Yee-Shin, Yoshimori Tamotsu
Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
PLoS Pathog. 2017 Jul 6;13(7):e1006444. doi: 10.1371/journal.ppat.1006444. eCollection 2017 Jul.
Group A Streptococcus (GAS) is deleterious pathogenic bacteria whose interaction with blood vessels leads to life-threatening bacteremia. Although xenophagy, a special form of autophagy, eliminates invading GAS in epithelial cells, we found that GAS could survive and multiply in endothelial cells. Endothelial cells were competent in starvation-induced autophagy, but failed to form double-membrane structures surrounding GAS, an essential step in xenophagy. This deficiency stemmed from reduced recruitment of ubiquitin and several core autophagy proteins in endothelial cells, as demonstrated by the fact that it could be rescued by exogenous coating of GAS with ubiquitin. The defect was associated with reduced NO-mediated ubiquitin signaling. Therefore, we propose that the lack of efficient clearance of GAS in endothelial cells is caused by their intrinsic inability to target GAS with ubiquitin to promote autophagosome biogenesis for xenophagy.
A组链球菌（GAS）是有害的致病细菌，其与血管的相互作用会导致危及生命的菌血症。虽然自噬的一种特殊形式——异噬作用可清除上皮细胞中入侵的GAS，但我们发现GAS能够在内皮细胞中存活并繁殖。内皮细胞能够进行饥饿诱导的自噬，但未能形成围绕GAS的双膜结构，而这是异噬作用的关键步骤。这种缺陷源于内皮细胞中泛素和几种核心自噬蛋白的募集减少，这一事实表明，通过用泛素对GAS进行外源性包被可以挽救这种缺陷。该缺陷与一氧化氮介导的泛素信号传导减少有关。因此，我们认为内皮细胞中缺乏对GAS的有效清除是由于其内在无法用泛素靶向GAS以促进自噬体生物发生从而进行异噬作用所致。
