Shigella flexneri suppresses NF-κB activation by inhibiting linear ubiquitin chain ligation.

Abstract

The Linear Ubiquitin chain Assembly Complex (LUBAC) is a multimeric E3 ligase that catalyzes M1- or linear ubiquitination of activated immune receptor signaling complexes (RSCs). While mutations that disrupt linear ubiquitin assembly lead to complex disease pathologies including immunodeficiency and autoinflammation in both humans and mice, microbial toxins that target LUBAC function have not yet been discovered. Here, we report the identification of two homologous Shigella flexneri Type III Secretion System (T3SS) effector E3 ligases IpaH1.4 and IpaH2.5 that directly interact with LUBAC subunit HOIL-1L (RBCK1) and conjugate K48-linked ubiquitin chains to the catalytic RING-between-RING domain of HOIP (RNF31). Proteasomal degradation of HOIP leads to irreversible inactivation of linear ubiquitination and blunting of NF-κB nuclear translocation in response to TNF, IL-1β, and pathogen associated molecular patterns (PAMPs). Loss of function studies in mammalian cells in combination with bacterial genetics explains how Shigella evades a broad spectrum of immune surveillance systems by cooperative inhibition of receptor ubiquitination, and reveals the critical importance of LUBAC in host defense against pathogens.