期刊
AUTOPHAGY
卷 16, 期 2, 页码 334-346出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2019.1628539
关键词
Autophagy; group A Streptococcus; NAD-glycohydrolase; RAB GTPase
类别
资金
- Japan Agency for Medical Research and Development [18fk0108073h0001, 18fm0208030h0002, 19fk0108073h0002, 19fm0208030h0003, 19fk0108044h0203]
- Japan Society for the Promotion of Science [16K08775, 26462776, 17K19552, 16H05188, 15K15130, 18K07109, 19H03471]
- Yakult Bio-Science Foundation
- Joint Research Project of the Institute of Medical Science, the University of Tokyo
- Takeda Science Foundation
- Grants-in-Aid for Scientific Research [18K07109, 19H03471, 15K15130, 16K08775, 16H05188, 26462776, 17K19552] Funding Source: KAKEN
Autophagy selectively targets invading bacteria to defend cells, whereas bacterial pathogens counteract autophagy to survive in cells. The initiation of canonical autophagy involves the PIK3C3 complex, but autophagy targeting Group A Streptococcus (GAS) is PIK3C3-independent. We report that GAS infection elicits both PIK3C3-dependent and -independent autophagy, and that the GAS effector NAD-glycohydrolase (Nga) selectively modulates PIK3C3-dependent autophagy. GAS regulates starvation-induced (canonical) PIK3C3-dependent autophagy by secreting streptolysin O and Nga, and Nga also suppresses PIK3C3-dependent GAS-targeting-autophagosome formation during early infection and facilitates intracellular proliferation. This Nga-sensitive autophagosome formation involves the ATG14-containing PIK3C3 complex and RAB1 GTPase, which are both dispensable for Nga-insensitive RAB9A/RAB17-positive autophagosome formation. Furthermore, although MTOR inhibition and subsequent activation of ULK1, BECN1, and ATG14 occur during GAS infection, ATG14 recruitment to GAS is impaired, suggesting that Nga inhibits the recruitment of ATG14-containing PIK3C3 complexes to autophagosome-formation sites. Our findings reveal not only a previously unrecognized GAS-host interaction that modulates canonical autophagy, but also the existence of multiple autophagy pathways, using distinct regulators, targeting bacterial infection.
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