http://www.cell.com/article/S009286742300421X/pdf

A 360° view of the inflammasome: Mechanisms of activation, cell death, and diseases

http://www.cell.com/article/S009286742300524X/pdf

NLRP12-PANoptosome activates PANoptosis and pathology in response to heme and PAMPs

Human NLRP1 (NACHT, LRR, and PYD domain-containing protein 1) is an innate immune sensor predominantly expressed in the skin and airway epithelium. Here, we report that human NLRP1 senses the ultraviolet B (UVB)- and toxin-induced ribotoxic stress response (RSR). Biochemically, RSR leads to the direct hyperphosphorylation of a human-specific disordered linker region of NLRP1 (NLRP1DR) by MAP3K20/ZAKα kinase and its downstream effector, p38. Mutating a single ZAKα phosphorylation site in NLRP1DR abrogates UVB- and ribotoxin-driven pyroptosis in human keratinocytes. Moreover, fusing NLRP1DR to CARD8, which is insensitive to RSR by itself, creates a minimal inflammasome sensor for UVB and ribotoxins. These results provide insight into UVB sensing by human skin keratinocytes, identify several ribotoxins as NLRP1 agonists, and establish inflammasome-driven pyroptosis as an integral component of the RSR. Description Sunburn: a ZAK attack Nod-like receptors (NLRs) are intracellular sensors of infection that, when activated, assemble into signaling complexes (inflammasomes) that induce proinflammatory cytokine production and pyroptotic cell death. One such NLR, NLRP1, is expressed in the skin and can be triggered by ultraviolet B (UVB) radiation, the cause of acute sunburn. Robinson et al. report that UVB-induced RNA photolesions stall ribosomes, activating the ribotoxic stress response kinase ZAKα. Together with p38, ZAKα directly phosphorylates the disordered linker region of human NLRP1. Several microbial ribotoxins also trigger this pathway, suggesting that it may serve as a target for future anti-inflammatory therapies. —STS Part of the human inflammasome, an innate immune sensor complex, senses the ribotoxic stress response.

ZAKα-driven ribotoxic stress response activates the human NLRP1 inflammasome

The innate immune system detects pathogens via germline-encoded receptors that bind to conserved pathogen ligands called pathogen-associated molecular patterns (PAMPs). Here we consider an additional strategy of pathogen sensing called effector-triggered immunity (ETI). ETI involves detection of pathogen-encoded virulence factors, also called effectors. Pathogens produce effectors to manipulate hosts to create a replicative niche and/or block host immunity. Unlike PAMPs, effectors are often diverse and rapidly evolving and can thus be unsuitable targets for direct detection by germline-encoded receptors. Effectors are instead often sensed indirectly via detection of their virulence activities. ETI is a viable strategy for pathogen sensing and is used across diverse phyla, including plants, but the molecular mechanisms of ETI are complex compared to simple receptor/ligand-based PAMP detection. Here we survey the mechanisms and functions of ETI, with a particular focus on emerging insights from animal studies. We suggest that many examples of ETI may remain to be discovered, hiding in plain sight throughout immunology. Expected final online publication date for the Annual Review of Immunology, Volume 41 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Effector-Triggered Immunity.

Nucleotide-binding oligomerization domain (NOD)-like receptors, also known as nucleotide-binding leucine-rich repeat receptors (NLRs), are a family of cytosolic pattern recognition receptors that detect a wide variety of pathogenic and sterile triggers. Activation of specific NLRs initiates pro- or anti-inflammatory signaling cascades and the formation of inflammasomes-multi-protein complexes that induce caspase-1 activation to drive inflammatory cytokine maturation and lytic cell death, pyroptosis. Certain NLRs and inflammasomes act as integral components of larger cell death complexes-PANoptosomes-driving another form of lytic cell death, PANoptosis. Here, we review the current understanding of the evolution, structure, and function of NLRs in health and disease. We discuss the concept of NLR networks and their roles in driving cell death and immunity. An improved mechanistic understanding of NLRs may provide therapeutic strategies applicable across infectious and inflammatory diseases and in cancer. 

The NLR family of innate immune and cell death sensors.

The ZAKα-driven ribotoxic stress response (RSR) is activated by ribosome stalling and/or collisions. Recent work demonstrates that RSR also plays a role in innate immunity by activating the human NLRP1 inflammasome. Here, we report that ZAKα and NLRP1 sense bacterial exotoxins that target ribosome elongation factors. One such toxin, diphtheria toxin (DT), the causative agent for human diphtheria, triggers RSR-dependent inflammasome activation in primary human keratinocytes. This process requires iron-mediated DT production in the bacteria, as well as diphthamide synthesis and ZAKα/p38-driven NLRP1 phosphorylation in host cells. NLRP1 deletion abrogates IL-1β and IL-18 secretion by DT-intoxicated keratinocytes, while ZAKα deletion or inhibition additionally limits both pyroptotic and inflammasome-independent non-pyroptotic cell death. Consequently, pharmacologic inhibition of ZAKα is more effective than caspase-1 inhibition at protecting the epidermal barrier in a 3D skin model of cutaneous diphtheria. In summary, these findings implicate ZAKα-driven RSR and the NLRP1 inflammasome in antibacterial immunity and might explain certain aspects of diphtheria pathogenesis. 

Diphtheria toxin activates ribotoxic stress and NLRP1 inflammasome-driven pyroptosis.

NLRP1 is an innate immune sensor protein that activates inflammasome-driven pyroptotic cell death. Recent work demonstrates that human NLRP1 has evolved to sense viral infections. Whether and how human NLRP1 responds to other infectious agents is unclear. Here, and in a companion manuscript, we report that human NLRP1, as an integral component of the ribotoxic stress response (RSR), is activated by bacterial exotoxins that target human ribosome elongation factors EEF1 and EEF2, including Diphtheria Toxin (DT) from Corynebacterium diphtheriae, exotoxin A from Pseudomonas aeruginosa and sidI from Legionella pneumophila. In human keratinocytes, DT activates RSR kinases ZAKα, p38 and JNKs, upregulates a set of signature RSR transcripts and triggers rapid NLRP1-dependent pyroptosis. Mechanistically, these processes require 1) DtxR-mediated de-repression of DT production in the bacteria, as well as 2) diphthamide synthesis and 3) ZAKα/p38-driven NLRP1 phosphorylation in the host. In 3D human skin cultures, Corynebacterium diphtheriae infection disrupts barrier function and induces IL-1 driven inflammation. Pharmacologic inhibition of p38 and ZAKα suppresses keratinocyte pyroptosis and rescues barrier integrity of Corynebacterium diphtheriae-treated organotypic skin. In summary, these findings implicate RSR and the NLRP1 inflammasome in antibacterial innate immunity and might explain certain aspects of diphtheria pathogenesis. KEY POINTS EEF1/EEF2-targeting bacterial exotoxins activate the human NLRP1 inflammasome. DT+ve toxigenic Corynebacterium diphtheriae induces ZAKα-driven RSR and NLRP1-driven pyroptosis in human keratinocytes. Identification of transcripts that are induced by multiple RSR agents across multiple cell types. p38 and ZAKα inhibition rescues epidermal integrity by limiting pyroptosis in 3D skin mode of cutaneous diphtheria.

/pdf/corynebacterium-diphtheriae-causes-keratinocyte-intrinsic-1ivyoiy7.pdf

Corynebacterium diphtheriae causes keratinocyte-intrinsic ribotoxic stress and NLRP1 inflammasome activation in a model of cutaneous diphtheria

Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses. The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation in the skin. We found that diverse stress signals converge on the activation of p38 kinases to initiate human NLRP1 inflammasome assembly: UV irradiation and microbial molecules that initiate the ribotoxic stress response critically relied on the MAP3 kinase ZAKα to activate p38 and ultimately human NLRP1. Infection with insect-transmitted alphaviruses, including Semliki Forest, Ross River, and Chikungunya virus, also activated NLRP1 in a p38-dependent manner. In the absence on ZAKα, inflammasome assembly was maintained, although at reduced levels, indicating contribution of other upstream kinases. NLRP1 activation by direct nanobody-mediated ubiquitination was independent of p38 activity. Stimulation of p38 by overexpression of MAP2 kinases MKK3 or MKK6 is sufficient for NLRP1 activation, and NLRP1 is directly phosphorylated by p38. Taken together, we define p38 activation as a unifying signaling hub that controls NLRP1 inflammasome activation by integrating a variety of cellular stress signals relevant to the skin.

/pdf/p38-kinases-mediate-nlrp1-inflammasome-activation-after-1zg39kde.pdf

P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Jacob Mayer

Author Tools

Chat about Author

Papers

Diphtheria toxin activates ribotoxic stress and NLRP1 inflammasome-driven pyroptosis.

Corynebacterium diphtheriae causes keratinocyte-intrinsic ribotoxic stress and NLRP1 inflammasome activation in a model of cutaneous diphtheria

P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection