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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Bacterial Proteins / metabolism
  • Cell Line
  • Epithelial Cells / immunology*
  • Epithelial Cells / microbiology
  • Humans
  • Nedd4 Ubiquitin Protein Ligases / metabolism*
  • Polyubiquitin / metabolism*
  • Streptococcus pneumoniae / immunology*
  • Streptolysins / metabolism*
  • Ubiquitination
  • rab GTP-Binding Proteins / metabolism*


  • Bacterial Proteins
  • Streptolysins
  • plY protein, Streptococcus pneumoniae
  • Polyubiquitin
  • Nedd4 Ubiquitin Protein Ligases
  • Nedd4 protein, human
  • RAB41 protein, human
  • rab GTP-Binding Proteins