Abstract
Mammals and plants share pathogen-sensing systems named nod-like receptors (NLRs). Some NLRs form the inflammasome, a protein scaffold that regulates the secretion of interleukin (IL)-1β and IL-18 by cleaving catalytically inactive substrates into mature cytokines. Here, we show an immune conservation between plant and mammalian NLRs and demonstrate that the murine nuclear receptor binding SET domain protein 1 (NSD1), a protein that bears similarity to the NLR regulator enhanced downy mildew 2 (EDM2) in Arabidopsis, diminishes caspase-1 activity during extracellular stimulation with Listeria monocytogenes listeriolysin O (LLO). EDM2 is known to regulate plant developmental processes, whereas NSD1 is associated with developmental disorders. We observed that NSD1 neither affects nuclear factor (NF)-κB signaling nor regulates NLRP3 inflammasome gene expression at the chromatin, transcriptional or translational level during LLO stimulation of macrophages. Silencing of Nsd1 followed by LLO stimulation led to increased caspase-1 activation, enhanced post-translational maturation of IL-1β and IL-18 and elevated pyroptosis, a form of cell death associated with inflammation. Furthermore, treatment of macrophages with LLOW492A, which lacks hemolytic activity due to a tryptophan to alanine substitution in the undecapeptide motif, indicates the importance of functional LLO for NSD1 regulation of the NLRP3 inflammasome. Taken together, our results indicate that NLR signaling in plants may be used for gene discovery in mammals.
Highlights
The inflammasome is a critical component of the innate immune system that provides immediate protection against an infectious insult or cellular damage [1]
listeriolysin O (LLO) stimulation of macrophages upregulates nuclear receptor binding SET domain protein 1 (NSD1) Since L. monocytogenes LLO is important for bacterial virulence
Our results suggest that: (1) WT L. monocytogenes elicits low levels of IL-1b secretion; and (2) flagellin and LLO are seemingly important for NLRC4 and NLRP3 recognition in mouse macrophages
Summary
The inflammasome is a critical component of the innate immune system that provides immediate protection against an infectious insult or cellular damage [1]. The canonical protein scaffold is formed by nod-like (NLRs) or an absent-in-melanoma 2 (AIM2) receptors, the apoptosis-associated speck-like protein (ASC) and caspase-1. Inflammasome activation leads to the release of interleukin (IL)-1b and IL-18 and occurs as a two-tier system [2]. The first signal (priming) involves the activation of the nuclear factor (NF)-kB pathway, which induces the transcription and translation of pro-inflammatory cytokines and other genes. Inflammasome activation results in the maturation of IL-1b and IL-18 by the enzyme caspase-1 [3,4]. Compared to the classical NLRC4, NLRP1 and AIM2 inflammasomes [5], NLRP3 is uniquely activated by innumerable stimulants, ranging from danger signals to bacterial structures and pore-forming toxins [6]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
