Shigella effector IpaH4.5 targets 19S regulatory particle subunit RPN13 in the 26S proteasome to dampen cytotoxic T lymphocyte activation

Cell Microbiol. 2019 Mar;21(3):e12974. doi: 10.1111/cmi.12974. Epub 2018 Dec 5.


Subversion of antigen-specific immune responses by intracellular pathogens is pivotal for successful colonisation. Bacterial pathogens, including Shigella, deliver effectors into host cells via the type III secretion system (T3SS) in order to manipulate host innate and adaptive immune responses, thereby promoting infection. However, the strategy for subverting antigen-specific immunity is not well understood. Here, we show that Shigella flexneri invasion plasmid antigen H (IpaH) 4.5, a member of the E3 ubiquitin ligase effector family, targets the proteasome regulatory particle non-ATPase 13 (RPN13) and induces its degradation via the ubiquitin-proteasome system (UPS). IpaH4.5-mediated RPN13 degradation causes dysfunction of the 19S regulatory particle (RP) in the 26S proteasome, inhibiting guidance of ubiquitinated proteins to the proteolytically active 20S core particle (CP) of 26S proteasome and thereby suppressing proteasome-catalysed peptide splicing. This, in turn, reduces antigen cross-presentation to CD8+ T cells via major histocompatibility complex (MHC) class I in vitro. In RPN13 knockout mouse embryonic fibroblasts (MEFs), loss of RPN13 suppressed CD8+ T cell priming during Shigella infection. Our results uncover the unique tactics employed by Shigella to dampen the antigen-specific cytotoxic T lymphocyte (CTL) response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Bacterial / metabolism*
  • Bacterial Proteins / metabolism*
  • Cells, Cultured
  • Cluster Analysis
  • DNA, Ribosomal / chemistry
  • DNA, Ribosomal / genetics
  • Disease Models, Animal
  • Dysentery, Bacillary / microbiology
  • Dysentery, Bacillary / pathology
  • Host-Pathogen Interactions*
  • Humans
  • Immune Evasion*
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Lymphocyte Activation
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Theoretical
  • Phylogeny
  • Proteasome Endopeptidase Complex / metabolism*
  • RNA, Ribosomal / genetics
  • Sequence Analysis, DNA
  • Shigella flexneri / growth & development*
  • Shigella flexneri / immunology
  • Shigella flexneri / pathogenicity
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / microbiology
  • Virulence Factors / metabolism


  • Adrm1 protein, mouse
  • Antigens, Bacterial
  • Bacterial Proteins
  • DNA, Ribosomal
  • Intracellular Signaling Peptides and Proteins
  • RNA, Ribosomal
  • RNA, ribosomal, 26S
  • Virulence Factors
  • ipaH protein, Shigella flexneri
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease