期刊
AUTOPHAGY
卷 15, 期 3, 页码 466-477出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2018.1532260
关键词
GcAV; group A Streptococcus; PI4KB; trans-Golgi network; xenophagy
类别
资金
- Takeda Science Foundation [16H05188, 15K15130, 26462776, 17K19552]
- Yakult Bio-Science Foundation
- Institute of Medical Science, the University of Tokyo
- Research Program on Emerging and Re-emerging Infectious Diseases [18fk0108044h0202, 18fk0108073h0001]
- J-PRIDE from Japan Agency for Medical Research and development, AMED [18fm0208030h0002]
Macroautophagy/autophagy plays an important role in the immune response to invasion by intracellular pathogens such as group A Streptococcus (GAS; Streptococcus pyogenes). We previously identified RAB30, a Golgi-resident GTPase, as a novel anti-bacterial autophagic regulator in the formation of GAS-containing autophagosome-like vacuoles (GcAVs); however, the precise mechanism underlying this process remains elusive. Here, we elucidate a novel property of RAB30: the ability to recruit PI4KB (phosphatidylinositol 4-kinase beta) to the Golgi apparatus and GcAVs. We found that trans-Golgi network (TGN) vesicles were incorporated into GcAVs via RAB30 to promote GcAV formation. Moreover, depletion of phosphatidylinositol-4-phosphate (PtdIns4P), a phosphatidylinositol enriched in the TGN, by wortmannin and phenylarsine oxide, followed by subsequent repletion with exogenous PtdIns4P revealed that PtdIns4P is crucial for GcAV formation. Furthermore, we identify an interaction between RAB30 and PI4KB, in which the knockdown of RAB30 decreased the localization of PI4KB to the TGN and GcAVs. Finally, PI4KB knockout suppressed autophagy by inhibiting GcAV formation, resulting in the increased survival of GAS. Our results demonstrate a novel autophagosomal formation mechanism involving coordinative functions of RAB30 and PI4KB distinct from those utilized in canonical autophagy.
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