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Cell Microbiol. 2018 Aug;20(8):e12846. doi: 10.1111/cmi.12846. Epub 2018 Apr 22.

Molecular mechanisms of Streptococcus pneumoniae-targeted autophagy via pneumolysin, Golgi-resident Rab41, and Nedd4-1-mediated K63-linked ubiquitination.

Author information

1
Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo, Japan.
2
Department of Health Sciences, Saitama Prefectural University, Saitama, Japan.
3
Department of Life Science and Medical Bioscience, Waseda University, Tokyo, Japan.
4
School of Veterinary Medicine, Azabu University, Sagamihara-shi, Kanagawa, Japan.
5
Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama-shi, Kanagawa, Japan.
6
Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo, Japan.
7
Division of Veterinary Hygiene and Public Health, Department of Preventive Veterinary Medicine, School of Veterinary Medicine, Faculty of Veterinary Science, Nippon Veterinary and Life Science University, Tokyo, Japan.
8
Division of Ultrastructural Research, BioMedical Research Center, Juntendo University, Tokyo, Japan.
9
Department of Cell Biology and Neuroscience, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
10
Laboratory of Animal Applied Microbiology, Graduate School of Environmental and Life Science, Okayama University, Okayama, Japan.
11
Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
12
Department of Immunoparasitology, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
13
Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
14
Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
15
Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi, Japan.
16
Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Gottingen, Germany.

Abstract

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.

KEYWORDS:

K48- and K63-linked polyUb chain; Nedd4-1; Rab41 (Rab43); Streptococcus pneumoniae; pneumolysin; selective autophagy

PMID:
29582580
DOI:
10.1111/cmi.12846

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