Endothelial cells are intrinsically defective in xenophagy of Streptococcus pyogenes

Shiou-Ling Lu; Tsuyoshi Kawabata; Yi-Lin Cheng; Hiroko Omori; Maho Hamasaki; Tatsuya Kusaba; Ryo Iwamoto; Hirokazu Arimoto; Takeshi Noda; Yee-Shin Lin; Tamotsu Yoshimori

doi:10.1371/journal.ppat.1006444

Endothelial cells are intrinsically defective in xenophagy of Streptococcus pyogenes

PLoS Pathog. 2017 Jul 6;13(7):e1006444. doi: 10.1371/journal.ppat.1006444. eCollection 2017 Jul.

Authors

Shiou-Ling Lu¹, Tsuyoshi Kawabata², Yi-Lin Cheng^{3

4}, Hiroko Omori⁵, Maho Hamasaki², Tatsuya Kusaba¹, Ryo Iwamoto¹, Hirokazu Arimoto⁶, Takeshi Noda^{7

8}, Yee-Shin Lin^{3

9}, Tamotsu Yoshimori^{1

2}

Affiliations

¹ Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
² Department of Genetics, Graduate School of Medicine, Osaka University, Osaka, Japan.
³ Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁴ Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National-Yang Ming University, Taipei, Taiwan.
⁵ Research Institute for Microbial Disease, Osaka University, Osaka, Japan.
⁶ Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
⁷ Graduate School of Frontier Bioscience, Osaka University, Osaka, Japan.
⁸ Center for Frontier Oral Science, Graduate School of Dentistry, Osaka University, Osaka, Japan.
⁹ Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.

Abstract

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.

MeSH terms

Autophagy*
Cell Line
Endothelial Cells / cytology*
Endothelial Cells / metabolism
Endothelial Cells / microbiology
Epithelial Cells / cytology
Epithelial Cells / metabolism
Epithelial Cells / microbiology
Host-Pathogen Interactions
Humans
Phagosomes / metabolism
Phagosomes / microbiology
Streptococcal Infections / metabolism
Streptococcal Infections / microbiology
Streptococcal Infections / physiopathology*
Streptococcus pyogenes / genetics
Streptococcus pyogenes / physiology*
Ubiquitin / metabolism

Substances

Ubiquitin

Grants and funding

This work was supported by the Ministry of Education, Culture, Sports, Science and Technology of Japan (Grant-in-Aid for Scientific Research: 25111002, URL: https://www.jsps.go.jp/english/e-grants/) to TY and AMED-CREST from Japan Agency for Medical Research and Development, AMED (http://www.amed.go.jp/en/) to TY. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.