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

AbstractSubversion of antigen ‐specific immune responses by intracellular pathogens is pivotal for successful colonization. Bacterial pathogens, includingShigella, 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 thatShigella 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 partic le (CP) of 26S proteasome and thereby suppressing proteasome‐catalyzed peptide splicing. This, in turn, reduces antigen cross‐presentation to CD8+ T cells via major histocompatibility complex (MHC) class Iin vitro. In RPN13 knockout mouse embryonic fibroblasts (MEFs), loss of RPN13 suppressed CD8+ T cell priming duringShigella infection. Our results uncover the unique tactics employed byShigella to dampen the antigen ‐specific cytotoxic T lymphocyte (CTL) response.
Source: Cellular Microbiology - Category: Microbiology Authors: Tags: RESEARCH ARTICLE Source Type: research