Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages

• DOI: 10.1073/pnas.1324021111
• Publication Date: 2014-09-23T07:21:36Z
• Authors: Shiho Suzuki; Hitomi Mimuro; Minsoo Kim; Michinaga Ogawa; Hiroshi Ashida; Takahito Toyotome; Luigi Franchi; Masato Suzuki; Takahito Sanada; Toshihiko Suzuki; Hiroko Tsutsui; Gabriel Núñez; Chihiro Sasakawa
• Keywords: NLRC4; Pyrin domain; AIM2; Flagellin

Significance Shigella modulates macrophage cell death by activating nucleotide-binding oligomerization domain–like receptor (NLR) inflammasome to secure its own dissemination. Here we report that invasion plasmid antigen H7.8 (IpaH7.8) plays a central role in inducing via activation of NLR family pyrin domain-containing 3 and CARD 4 inflammasomes an IpaH7.8 enzyme (E3) ligase-dependent manner. Importantly, IpaH7.8-deficient mutant was unable egress from macrophages efficiently, resulting delayed bacterial multiplication. We identified glomulin—a member the S-phase kinase-associated protein 1–F-box–like complex originally as required for normal vascular development—as target E3 ligase-mediated polyubiquitination, which leads activation. In vitro vivo studies confirmed IpaH7.8-mediated glomulin degradation during infection activated promoted death.