The Shigella Type III Secretion Effector IpaH4.5 Targets NLRP3 to Activate Inflammasome Signaling.

Xiaolin Wang,Mingxin Dong,Min Min,Yanhong Zhang,Xiaoli Yang,Haotian Lin,Kai Guan,Jin Sun,Xiang He,Zhenxue Sun,Xiaopan Yang,Bin Wang,Congwen Wei,Hui Zhong,Luming Wan

doi:10.3389/fcimb.2020.511798

Xiaolin Wang, Mingxin Dong + Show 13 more

Open Access

https://doi.org/10.3389/fcimb.2020.511798

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Abstract

Activation of the NLRP3 inflammasome requires the expression of NLRP3, which is strictly regulated by its capacity to directly recognize microbial-derived substances. Even though the involvement of caspase-1 activation in macrophages via NLRP3 and NLRC4 has been discovered, the accurate mechanisms by which Shigella infection triggers NLRP3 activation remain inadequately understood. Here, we demonstrate that IpaH4.5, a Shigella T3SS effector, triggers inflammasome activation by regulating NLRP3 expression through the E3 ubiquitin ligase activity of IpaH4.5. First, we found that IpaH4.5 interacted with NLRP3. As a result, IpaH4.5 modulated NLRP3 protein stability and inflammasome activation. Bacteria lacking IpaH4.5 had dramatically reduced ability to induce pyroptosis. Our results identify a previously unrecognized target of IpaH4.5 in the regulation of inflammasome signaling and clarify the molecular basis for the cytosolic response to the T3SS effector.

Highlights

Innate immunity is the first barrier of the body against the invasion of pathogenic microorganisms
We found that overexpression of IpaH4.5 in RAW264.7 macrophages significantly increased the release of lactate dehydrogenase (LDH), which is a marker of pyroptosis (Figure 5A)
Previous work had established the molecular function of IpaH7.8 in the context of activating inflammasomes by targeting glomulin as an E3 ubiquitin ligase (Suzuki et al, 2014)

Summary

Introduction

Innate immunity is the first barrier of the body against the invasion of pathogenic microorganisms. As an important component of the innate immune system, innate immune cells recognize pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs), followed by secreting cytokines and antimicrobial intermediates (Thompson et al, 2011). Among all kinds of PRRs, nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are cytoplasmic proteins that recognize specific PAMPs and activate pro-inflammatory and antimicrobial immune responses (Franchi et al, 2008; Caruso et al, 2014). Typical activation of the NLRP3 inflammasome can be described as follows: in response to PAMP recognition, NLRs bind to adaptor apoptosis-associated speck-like protein (ASC) by PYD-PYD interactions, which form the NLRP3 inflammasome, recruiting pro-caspase-1, and activating caspase-1 (Maharana et al, 2017; Taghavi et al, 2017). Afterwards, caspase-1 induces IL-1β production and causes a series of cellular events such as pyroptosis (Srinivasula et al, 2002)

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