1) Nod-like receptors (NLRs) are cytosolic pattern recognition receptors that detect microbial and danger signals. Recent evidence suggests that some NLRs are activated at the level of host membranes or as a consequence of membrane damage.
2) Studies have found that the NLR proteins Nod1 and Nod2 localize to plasma membranes upon activation by bacterial ligands. Membrane localization is important for their ability to trigger inflammatory signaling pathways.
3) The NLRs NLRP3 and NLRP1 are thought to detect potassium efflux and reactive oxygen species near plasma membranes in response to cellular stresses. NLRP3 can also be activated by lysosomal damage, suggesting a role in sensing membrane integrity.
Inflammasomes: Guardian Angels of the bodyVarij Nayan
"Generally speaking, the inflammasome depends on the assembly of a sensor(e.g. NLRP), with an adaptor, ASC (apoptosis-associated Speck-like protein containing a CARD), allowing the recruitment and activation of an inflammatory caspase, Caspase-1"
Inflammasomes: Guardian Angels of the bodyVarij Nayan
"Generally speaking, the inflammasome depends on the assembly of a sensor(e.g. NLRP), with an adaptor, ASC (apoptosis-associated Speck-like protein containing a CARD), allowing the recruitment and activation of an inflammatory caspase, Caspase-1"
— The central dogma of molecular biology states that DNA makes RNA and RNA makes protein. Recently, a large number of RNAs have been identified in animal and plants that have little or no protein – coding potential. Such RNA molecules have been discovered by the extensive applications of high – throughput sequencing technology. Non – coding RNAs (ncRNAs), which comprise a significant output of the genomes of prokaryotes and especially eukaryotes, are increasingly implicated in the molecular mechanisms that are being used for responding to biotic and abiotic stresses that occurred in living things life. The ncRNAs are a heterogeneous group of RNA molecules, which can be classified in different ways according to their location, length, and biological functions. In this review a brief description about non – coding RNAs will be brought especially in plants.
Role of molecular marker play a significant supplementary role in enhancing yield along with conventional plant breeding methods. the result obtain through molecular method are more accurate and at genotypic level. It had wider applications in field of plant breeding, biotechnology, physiology, pathology, entamology, etc. The mapping information obtained from these markers had created a revolution in the sequencing sector and open many pathways for developments, innovations and research.
Nrf2 Transcription Factor- Nuclear Factor- Erythroid 2 related factor)PHARMA IQ EDUCATION
1. Nrf2- transcription factor
2. Reactive Oxygen Species
3. Free Radicals
4. Antioxidant Defence Mechanism
5. Function of Nrf2 receptor
6. Protein structural domain of Nrf2
7. Protein structural domain of Keap1
8. Physiological Role pf Nrf2
9.
THANK YOU
— The central dogma of molecular biology states that DNA makes RNA and RNA makes protein. Recently, a large number of RNAs have been identified in animal and plants that have little or no protein – coding potential. Such RNA molecules have been discovered by the extensive applications of high – throughput sequencing technology. Non – coding RNAs (ncRNAs), which comprise a significant output of the genomes of prokaryotes and especially eukaryotes, are increasingly implicated in the molecular mechanisms that are being used for responding to biotic and abiotic stresses that occurred in living things life. The ncRNAs are a heterogeneous group of RNA molecules, which can be classified in different ways according to their location, length, and biological functions. In this review a brief description about non – coding RNAs will be brought especially in plants.
Role of molecular marker play a significant supplementary role in enhancing yield along with conventional plant breeding methods. the result obtain through molecular method are more accurate and at genotypic level. It had wider applications in field of plant breeding, biotechnology, physiology, pathology, entamology, etc. The mapping information obtained from these markers had created a revolution in the sequencing sector and open many pathways for developments, innovations and research.
Nrf2 Transcription Factor- Nuclear Factor- Erythroid 2 related factor)PHARMA IQ EDUCATION
1. Nrf2- transcription factor
2. Reactive Oxygen Species
3. Free Radicals
4. Antioxidant Defence Mechanism
5. Function of Nrf2 receptor
6. Protein structural domain of Nrf2
7. Protein structural domain of Keap1
8. Physiological Role pf Nrf2
9.
THANK YOU
This presentation aims at giving a vivid knowledge about Nucleoli, a sub organelle of Nucleus, its role in protein formation. control, localization ad how specifically it is involved in Single Nucleotide polymorphism. The slide also discusses about the involvement of SNPs in Alzheimer’s Disease.
Presentation describes types of sn-RNA its classes,translation of sn-RNA,post translational mechanisms and its role in rna spliceosomal mediated splicing of RNA, and 3' end maturation of histone genes.It also gives information about different diseases related to sn-RNA
This course required us to present an article which prof gave us randomly. And my article is a review paper related to TLR signaling! I upload here just hope that it can be useful for someone who is interested in this approach for studyding TLR signaling dynamics based on Synthetic ligands!
Many thanks for your look at my presentation and leave some comments if I got mistakes inside!
Pushing the limits of ePRTC: 100ns holdover for 100 daysAdtran
At WSTS 2024, Alon Stern explored the topic of parametric holdover and explained how recent research findings can be implemented in real-world PNT networks to achieve 100 nanoseconds of accuracy for up to 100 days.
State of ICS and IoT Cyber Threat Landscape Report 2024 previewPrayukth K V
The IoT and OT threat landscape report has been prepared by the Threat Research Team at Sectrio using data from Sectrio, cyber threat intelligence farming facilities spread across over 85 cities around the world. In addition, Sectrio also runs AI-based advanced threat and payload engagement facilities that serve as sinks to attract and engage sophisticated threat actors, and newer malware including new variants and latent threats that are at an earlier stage of development.
The latest edition of the OT/ICS and IoT security Threat Landscape Report 2024 also covers:
State of global ICS asset and network exposure
Sectoral targets and attacks as well as the cost of ransom
Global APT activity, AI usage, actor and tactic profiles, and implications
Rise in volumes of AI-powered cyberattacks
Major cyber events in 2024
Malware and malicious payload trends
Cyberattack types and targets
Vulnerability exploit attempts on CVEs
Attacks on counties – USA
Expansion of bot farms – how, where, and why
In-depth analysis of the cyber threat landscape across North America, South America, Europe, APAC, and the Middle East
Why are attacks on smart factories rising?
Cyber risk predictions
Axis of attacks – Europe
Systemic attacks in the Middle East
Download the full report from here:
https://sectrio.com/resources/ot-threat-landscape-reports/sectrio-releases-ot-ics-and-iot-security-threat-landscape-report-2024/
UiPath Test Automation using UiPath Test Suite series, part 4DianaGray10
Welcome to UiPath Test Automation using UiPath Test Suite series part 4. In this session, we will cover Test Manager overview along with SAP heatmap.
The UiPath Test Manager overview with SAP heatmap webinar offers a concise yet comprehensive exploration of the role of a Test Manager within SAP environments, coupled with the utilization of heatmaps for effective testing strategies.
Participants will gain insights into the responsibilities, challenges, and best practices associated with test management in SAP projects. Additionally, the webinar delves into the significance of heatmaps as a visual aid for identifying testing priorities, areas of risk, and resource allocation within SAP landscapes. Through this session, attendees can expect to enhance their understanding of test management principles while learning practical approaches to optimize testing processes in SAP environments using heatmap visualization techniques
What will you get from this session?
1. Insights into SAP testing best practices
2. Heatmap utilization for testing
3. Optimization of testing processes
4. Demo
Topics covered:
Execution from the test manager
Orchestrator execution result
Defect reporting
SAP heatmap example with demo
Speaker:
Deepak Rai, Automation Practice Lead, Boundaryless Group and UiPath MVP
Observability Concepts EVERY Developer Should Know -- DeveloperWeek Europe.pdfPaige Cruz
Monitoring and observability aren’t traditionally found in software curriculums and many of us cobble this knowledge together from whatever vendor or ecosystem we were first introduced to and whatever is a part of your current company’s observability stack.
While the dev and ops silo continues to crumble….many organizations still relegate monitoring & observability as the purview of ops, infra and SRE teams. This is a mistake - achieving a highly observable system requires collaboration up and down the stack.
I, a former op, would like to extend an invitation to all application developers to join the observability party will share these foundational concepts to build on:
Elevating Tactical DDD Patterns Through Object CalisthenicsDorra BARTAGUIZ
After immersing yourself in the blue book and its red counterpart, attending DDD-focused conferences, and applying tactical patterns, you're left with a crucial question: How do I ensure my design is effective? Tactical patterns within Domain-Driven Design (DDD) serve as guiding principles for creating clear and manageable domain models. However, achieving success with these patterns requires additional guidance. Interestingly, we've observed that a set of constraints initially designed for training purposes remarkably aligns with effective pattern implementation, offering a more ‘mechanical’ approach. Let's explore together how Object Calisthenics can elevate the design of your tactical DDD patterns, offering concrete help for those venturing into DDD for the first time!
Why You Should Replace Windows 11 with Nitrux Linux 3.5.0 for enhanced perfor...SOFTTECHHUB
The choice of an operating system plays a pivotal role in shaping our computing experience. For decades, Microsoft's Windows has dominated the market, offering a familiar and widely adopted platform for personal and professional use. However, as technological advancements continue to push the boundaries of innovation, alternative operating systems have emerged, challenging the status quo and offering users a fresh perspective on computing.
One such alternative that has garnered significant attention and acclaim is Nitrux Linux 3.5.0, a sleek, powerful, and user-friendly Linux distribution that promises to redefine the way we interact with our devices. With its focus on performance, security, and customization, Nitrux Linux presents a compelling case for those seeking to break free from the constraints of proprietary software and embrace the freedom and flexibility of open-source computing.
Removing Uninteresting Bytes in Software FuzzingAftab Hussain
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In this work, we equipped AFL, a popular fuzzer, with DIAR and examined two critical Linux libraries -- Libxml's xmllint, a tool for parsing xml documents, and Binutil's readelf, an essential debugging and security analysis command-line tool used to display detailed information about ELF (Executable and Linkable Format). Our preliminary results show that AFL+DIAR does not only discover new paths more quickly but also achieves higher coverage overall. This work thus showcases how starting with lean and optimized seeds can lead to faster, more comprehensive fuzzing campaigns -- and DIAR helps you find such seeds.
- These are slides of the talk given at IEEE International Conference on Software Testing Verification and Validation Workshop, ICSTW 2022.
SAP Sapphire 2024 - ASUG301 building better apps with SAP Fiori.pdfPeter Spielvogel
Building better applications for business users with SAP Fiori.
• What is SAP Fiori and why it matters to you
• How a better user experience drives measurable business benefits
• How to get started with SAP Fiori today
• How SAP Fiori elements accelerates application development
• How SAP Build Code includes SAP Fiori tools and other generative artificial intelligence capabilities
• How SAP Fiori paves the way for using AI in SAP apps
Communications Mining Series - Zero to Hero - Session 1DianaGray10
This session provides introduction to UiPath Communication Mining, importance and platform overview. You will acquire a good understand of the phases in Communication Mining as we go over the platform with you. Topics covered:
• Communication Mining Overview
• Why is it important?
• How can it help today’s business and the benefits
• Phases in Communication Mining
• Demo on Platform overview
• Q/A
Sudheer Mechineni, Head of Application Frameworks, Standard Chartered Bank
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Epistemic Interaction - tuning interfaces to provide information for AI supportAlan Dix
Paper presented at SYNERGY workshop at AVI 2024, Genoa, Italy. 3rd June 2024
https://alandix.com/academic/papers/synergy2024-epistemic/
As machine learning integrates deeper into human-computer interactions, the concept of epistemic interaction emerges, aiming to refine these interactions to enhance system adaptability. This approach encourages minor, intentional adjustments in user behaviour to enrich the data available for system learning. This paper introduces epistemic interaction within the context of human-system communication, illustrating how deliberate interaction design can improve system understanding and adaptation. Through concrete examples, we demonstrate the potential of epistemic interaction to significantly advance human-computer interaction by leveraging intuitive human communication strategies to inform system design and functionality, offering a novel pathway for enriching user-system engagements.
LF Energy Webinar: Electrical Grid Modelling and Simulation Through PowSyBl -...DanBrown980551
Do you want to learn how to model and simulate an electrical network from scratch in under an hour?
Then welcome to this PowSyBl workshop, hosted by Rte, the French Transmission System Operator (TSO)!
During the webinar, you will discover the PowSyBl ecosystem as well as handle and study an electrical network through an interactive Python notebook.
PowSyBl is an open source project hosted by LF Energy, which offers a comprehensive set of features for electrical grid modelling and simulation. Among other advanced features, PowSyBl provides:
- A fully editable and extendable library for grid component modelling;
- Visualization tools to display your network;
- Grid simulation tools, such as power flows, security analyses (with or without remedial actions) and sensitivity analyses;
The framework is mostly written in Java, with a Python binding so that Python developers can access PowSyBl functionalities as well.
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- For beginners: discover PowSyBl's functionalities through a quick general presentation and the notebook, without needing any expert coding skills;
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This talk is aimed at encouraging a more independent approach to using PHP frameworks, moving towards a more flexible and future-proof approach to PHP development.
PHP Frameworks: I want to break free (IPC Berlin 2024)
3 nod
1. Available online at www.sciencedirect.com
Nod-like receptors: sentinels at host membranes
Dana J Philpott1 and Stephen E Girardin2
Innate immune detection of danger signals and microbial motifs transduction cascades, which include the pro-inflamma-
is achieved by distinct families of pattern recognition tory NF-kB (for Nod1 and Nod2) [2,3] and the caspase-1
molecules. These include the membrane-anchored Toll-like inflammasome (for NLRC4, NLRP3 and NLRP1) path-
receptors (TLRs), as well as cytosolic Nod-like receptors ways [4] as well as activation of autophagy (Nod1, Nod2
(NLRs) and Rig-I-like receptors (RLRs). The precise mode of and NLRC4) [5,6] and cell death (including NLRC4,
NLR activation in the host cytosol remains poorly defined, as NLRP1 and NLRP3) [5,7,8].
evidence of direct interaction between NLRs and danger- or
microbial-associated molecular patterns remains elusive. In the past few years, the identification of the nature of
However, a number of convergent observations now suggest the molecular patterns detected by NLRs has been the
that activation of some NLRs occurs at the level of host subject of intense investigations, and the key role of
membranes or as a consequence of membrane damage. This NLRs in the cytosolic detection of various MAMPs
review focuses on this emerging theme and discusses the and DAMPs is clearly emerging. Nod1 and Nod2 detect
functional consequences of innate immune sensing at the specific structures within bacterial peptidoglycan [2], and
vicinity of the membrane. NLRC4 senses bacterial flagellin [9] as well as the bac-
Addresses terial type III secretion apparatus [10]. The inflamma-
1
Department of Immunology, University of Toronto, Toronto, Canada some-triggering protein NLRP3 was shown to detect a
2
Department of Laboratory Medicine and Pathobiology, University of wide array of molecules, including ATP, potassium efflux,
Toronto, Toronto, Canada
muramyl dipeptide (MDP), bacterial toxins, xenocom-
Corresponding authors: Girardin, Stephen E pounds (silica, asbestos, and aluminium hydroxide), viral
(stephen.girardin@utoronto.ca) nucleic acids, b-amyloid fibrils and malarial hemozoin
(reviewed in [11,12]). NLRP1 was also found to be a
pleiotropic sensor, mediating the detection of anthrax
Current Opinion in Immunology 2010, 22:428–434 lethal toxin, MDP, and potassium efflux. The extremely
This review comes from a themed issue on diverse repertoire of the molecular triggers activating the
Host pathogens caspase-1 inflammasome led to the hypothesis that
Edited by Adolfo Garcia-Sastre and Philippe Sansonetti NLRP proteins must in fact be activated by common
upstream cellular events [12–14]. The NADPH-depend-
Available online 3rd June 2010
ent generation of reactive oxygen species (ROS) or rup-
0952-7915/$ – see front matter ture of the lysosomal membrane could represent such
# 2010 Elsevier Ltd. All rights reserved. common activators of the caspase-1 inflammasome. In
DOI 10.1016/j.coi.2010.04.010
support of the former, recent evidence has shown that
NLRP3 interacts with thioredoxin-interacting proteins
(TXNIP) through the ROS-induced liberation of this
protein from thioredoxin [15].
Innate immunity relies on the detection of danger- and
microbial-associated molecular patterns (DAMPs and The interest in NLR biology is also driven by the striking
MAMPs, respectively) by several families of secreted association between mutations or polymorphisms in NLR
or cellular pattern-recognition molecules (PRMs). Several or NLR-associated genes and human inflammatory dis-
classes of cellular PRMS are directly responsible for the orders, which underscores the importance of this family in
induction of signal transduction pathways that shape the the control of inflammation [16,17]. In particular, Nod2
innate immune response, and these include the type I has been identified as the first susceptibility gene for
transmembrane molecules of the Toll-like receptor Crohn’s disease (CD) and Blau syndrome, and mutations
(TLR) family as well as the cytosolic Nod-like receptors in Nlrp3 (also known as Cryopyrin or Cias1) are associated
(NLRs) and Rig-I-like receptors (RLRs) [1]. with several rare autoinflammatory disorders, including
Muckle–Wells syndrome, chronic infantile neurological
The NLR family cutaneous and articular syndrome (CINCA) and familial
NLRs are defined by the juxtaposition of a central cold urticaria (FCU), and common variants in Nlrp3 have
(NACHT) domain and C-terminal leucine-rich repeat also been recently associated with CD [16,17]. In
(LRR) domain [2,3]. Twenty-two NLR proteins are pre- addition, polymorphisms in Nod1 have been associated
sent in the human genome, which are further grouped with asthma and atopic eczema, and Nlrp1 was identified
into subfamilies on the basis of their N-terminal region. as a susceptibility gene for vitiligo, Addison’s disease and
Upon activation, NLR proteins trigger a number of signal type I diabetes [16,17].
Current Opinion in Immunology 2010, 22:428–434 www.sciencedirect.com
2. Sentinels at host membranes Philpott and Girardin 429
Signal transduction cascades triggered by NLR engage- demonstrated that enforced targeting of Rip2 to the
ment have been studied in detail. A general common plasma membrane was sufficient to trigger NF-kB [21].
mechanism of activation likely requires the (homo- or Similar results were also reported for Nod1, as both Nod1
hetero-) oligomerization of NLR proteins, resulting in the and the IKKg subunit of the IKK complex, critical for
recruitment of adaptor proteins, such as Rip2 for Nod1 NF-kB activation, were found enriched at the plasma
and Nod2, or ASC for NLRC4, NLRP1 and NLRP3 [2,3]. membrane, at the site of bacterial entry [22].
Rip2 is essential for mediating Nod1- and Nod2-depend-
ent activation of NF-kB and MAPK signaling [18], but is The consequence of targeting Nod protein to the plasma
dispensable for the Nod-driven recruitment of the autop- membrane is likely complex and dynamic. Indeed, relo-
hagosome at the site of bacterial entry in murine embryo- calization of Nod2 from a Triton-X-100 insoluble to
nic fibroblasts [6]. The exact requirement of ASC for soluble fractions with cytochalasin D, or exclusion of
NLRP and NLRC4 signaling is more complex, since this Nod2 from membrane ruffles, were found to correlate
adaptor protein was found to be either essential or dis- with enhanced capacity to trigger NF-kB pathways [23],
pensable in multiple models of NLR-dependent acti- suggesting that, in basal conditions, Nod-dependent
vation of the caspase-1 inflammasome [12]. activity might be locked out by membrane- or actin-
associated cofactors. In agreement for this, two indepen-
The nature of the events occurring upstream of NLR dent studies identified the membrane-associated protein
engagement, and in particular the exact mode of the Erbin as a Nod2-interacting protein, and demonstrated
detection of MAMPs or DAMPs by NLRs, remains less that Erbin acted as a negative modulator of Nod2-de-
understood. In the vast majority of cases, direct detection pendent pathways [24,25]. Other membrane-associated
or interaction between NLRs and either MAMPs or proteins have been shown to interact with Nod proteins
DAMPs has not been demonstrated. An exception to this and to modulate their function. The Rho GTPase Rac1,
was a recent study in which the authors performed an in which is essential for the regulation of membrane ruffling
vitro reconstitution of the NLRP1 inflammasome and and is also a component of the NADPH oxidase complex,
demonstrated oligomerization of NLRP1 and caspase-1 was found to interact with Nod2 and to negatively
through addition of MDP [19], therefore suggesting the regulate its function [23,26]. In contrast, the guanine
existence of a direct interaction between NLRP1 and exchange factor GEF-H1, which plays important roles
MDP. In the case of NLRP3, as discussed above, it is in RhoA activation in the context of Shigella invasion in
believed that secondary cellular events such as ROS- non-myeloid cells, was found to interact with Nod1 and
induced modifications or lysosomal damage might play positively modulate its function [27]. Finally, the protein
a key role in activation [12–14]. The cytosolic sub-cellular Duox2 of the NADPH oxidase complex was found to
localization where NLR engagement occurs is also not interact with Nod2 and to potentiate its function [28].
clearly established, because of the lack of sensitive tools The opposite effect of two members of the NADPH
to probe NLR activation by microscopy techniques. oxidase complex (Rac1 and Duox2) on Nod2-dependent
However, recent biochemical evidence points to a tight pathway remains unclear, but might reflect the more
relation between NLR activation and sub-cellular vicinity general impact of membrane targeting on Nod activity,
to plasma or internal membranes. An intriguing possib- acting as a negative or positive modulator of Nod function
ility would suggest that NLR localization at membranes is in resting versus ROS-generating or membrane-remodel-
not coincidental with NLR activation but actually a ing conditions, respectively (Figures 1 and 2).
prerequisite for physiological activation. The following
discussion reviews this hypothesis. NLRP1 and NLRP3
The functional relation between the activity of NLRP3
Evidence for the activation of NLRs at host and NLRP1 and host membranes is indirectly inferred by
membranes the nature of the MAMPs or DAMPs that they detect.
Nod1 and Nod2 Indeed, the fact that potassium efflux at the plasma
The first indication that NLRs function at host mem- membrane is sufficient to trigger NLRP3 and NLRP1
branes came from a study by Barnich et al. who demon- activation [29,30] is a strong indication that these NLRs
strated that Nod2-dependent responses to MDP are activated at the vicinity of the plasma membrane,
correlated with the capacity of the protein to localize where the dynamic variation of [K+] is the greatest.
to the plasma membrane [20]. Importantly, the authors Similarly, NADPH oxidase-dependent ROS levels likely
identified that the C-terminal end of the protein was diffuse poorly into the cytosolic space because of their
responsible for membrane targeting, therefore explaining unstable nature and the presence of a number of buffering
the defective MDP sensing capacity of the CD-associated cellular antioxidants. Therefore, NADPH-generated
Nod2 variant Nod2 3020insC, which lacks the last 33 ROS concentration must display a dynamic gradient
COOH-terminal amino acids of the protein. A recent resulting from the flux of their generation, with the
study further validated these observations by showing highest concentration found at the vicinity of the plasma
that Rip2 was also found at the plasma membrane, and or phagocytic membranes. Another interesting possibility
www.sciencedirect.com Current Opinion in Immunology 2010, 22:428–434
3. 430 Host pathogens
Figure 1
Activation of Nod1 and Nod2 at host membranes. Nod proteins can detect peptidoglycan fragments produced in host phagosome or phagolysosome
during degradation of phagocytosed bacteria. The nature of the transporters involved in the translocation of peptidoglycan from the phagolysosome to
the cytosol remains unknown. Peptidoglycan fragments in the extracellular milieu can also enter cells by endocytosis. In HEK293T cells, peptidoglycan
fragments translocate to the cytosol at least in part through the oligopeptide transporter SLC15A4. Nod proteins interact with membrane-associated
proteins GEF-H1, Erbin, as well as Rac1 and Duox2 from the NADPH oxidase complex. Nod1 and Nod2 also detect invading bacteria and trigger the
recruitment of the autophagic machinery (see also Figure 3).
would be that NLRP proteins could directly detect this, NLRC4 has been recently shown to detect directly
membrane damage or leakage. This idea is consistent the basal body rod component of the type III secretion
with the fact that several membrane toxins that insert into system apparatus of several Gram-negative bacteria, in-
host membranes, such as listeriolysin O, streptolysin O, a- cluding Salmonella typhimurium, Shigella flexneri and Pseu-
hemolysin or the anthrax lethal toxin were found to domonas aeruginosa. It must be noted that Naip5, another
trigger NLRP-dependent caspase-1 inflammasomes NLR protein previously identified as a critical protein
[12,13]. In addition, multiple lines of evidence point to implicated in the restriction of Legionella growth in macro-
a role of lysosomal damage and cytosolic leakage of phages, was also shown to participate in intracellular
cathepsin B in NLRP3 activation [13], suggesting that flagellin detection, together with NLRC4 [33].
NLRP protein may act as intracellular sensors of host
membrane integrity. NLRX1
NLRX1 localizes to mitochondria and is the only known
NLRC4 NLR protein that targets specifically a cellular organelle
NLRC4 was found to detect intracellular bacterial fla- [34,35]. Recent evidence demonstrated that NLRX1
gellin [31,32]. While this detection could in theory occur translocates to the mitochondrial matrix via its N-terminal
anywhere in the host cytosol in the case of flagellated addressing sequence and biochemical studies identified
bacteria that escape the phagocytic vacuole, it is inter- that the protein associates with the mitochondrial inner
esting to note that NLRC4 activation by Salmonella and membrane, at least in part, through its interaction with
Legionella requires both flagellin and functional type III or UQCRC2, a matrix-exposed core component of the com-
Type IV secretion systems, which insert into host mem- plex III of the respiratory chain [36]. It is possible that this
branes [31,32]. Together, these observations suggest that interaction contributes to the capacity of NLRX1 to
the detection of flagellin by NLRC4 might be functional regulate mitochondrial ROS generation, as previously
in the context of membrane damage. In agreement with demonstrated by over-expression studies. Finally, it has
Current Opinion in Immunology 2010, 22:428–434 www.sciencedirect.com
4. Sentinels at host membranes Philpott and Girardin 431
Figure 2
Activation of the inflammasome-triggering NLR proteins at host membranes. Bacterial processing in phagosome or phagolysosome generates
molecules (including peptidoglycan and flagellin) that translocate to the cytosol and trigger the caspase-1 inflammasome through NLRP3 and NLRC4/
NAIP5, respectively. NLRC4 also detects the structure of the type three secretion system (TTSS) inserted into the host membrane. A large variety of
molecules can also traffic through the host endocytic machinery to trigger NLRP3 and NLRP1 (see text for details). In this case, the mechanism
underlying inflammasome activation is not fully elucidated but is thought to involve NADPH oxidase-generated reactive oxygen species (ROS) or the
damage to the lysosomal membrane and the release of cathepsin B (cat B). Finally, potassium efflux (that can be triggered by the binding of ATP to the
purinergic receptors of the P2X family) also triggers NLRP3 through a mechanism likely involving ROS generation.
been proposed that NLRX1 could interact with the detected by NLR proteins [37,38]. It is likely that this site
antiviral protein MAVS, on the cytosolic side of the of translocation to the cytosol is physiologically critical for
mitochondrial outer membrane [34]. The capture of phagocytic cells; indeed, two recent reports demonstrate
NLRX1 by MAVS on its way to the mitochondrial matrix that the progressive degradation and processing of bac-
in certain conditions, such as viral infection, is an inter- teria or bacterial cell walls in the phagolysosome results in
esting hypothesis that awaits experimental evidence. the generation of peptidoglycan fragments that can trig-
ger either Nod2 [37] or NLRP3 [39] after cytosolic
Functional consequences of NLR signaling at translocation. However, the nature of the transporters
host membranes for MDP or other peptidoglycan motifs in the phagolyso-
NLRs as gatekeepers of endosomal or phagosomal some remains unknown. In HEK293T epithelial cells,
trafficking recent evidence demonstrated that Nod1 ligands are also
The intimate relation between host membrane dynamics internalized by clathrin-dependent endocytosis and are
and NLR activation has been recently illustrated by the exported to the cytosol from early endosomes, in part
observation that Nod ligands are internalized by clathrin- through the oligopeptide transporter SLC15A4 [40]. Stu-
mediated endocytosis and seem to be exported to the dies in other human epithelial cells similarly identified
cytosol in a specific manner. In the case of the Nod2 roles for other related transporters in mediating the trans-
ligand MDP, studies in macrophages suggest that the port of Nod ligands. Indeed, SLC15A1 and SLC15A2
molecule travels through the endocytic machinery up to were shown to transport MDP (in Caco-2 cells) [41,42]
lysosomes, where MDP is exported to the cytosol and is and iE-DAP (in upper airway epithelial cells) [43],
www.sciencedirect.com Current Opinion in Immunology 2010, 22:428–434
5. 432 Host pathogens
respectively. However, in the latter cases, the precise proteins Nod1 and Nod2 have been shown to play a key
mechanism of internalization and location of cytosolic role in mediating bacterial autophagy [6]. Indeed, these
export was not identified. Together, these recent findings NLR proteins were found to interact with the autophagy-
demonstrate that Nod-dependent activation is physio- nucleator protein ATG16L1, resulting in the recruitment
logically coupled with endocytic/phagocytic maturation of the proteins of the autophagic machinery at the site of
and bacterial cell wall degradation processes. It is con- bacterial entry (Figure 3). These results link Nod2 and
ceivable that the topological restriction of the cytosolic ATG16L1, two proteins whose genes have been associated
entry site (plasma membrane, early endosomes, and pha- with CD susceptibility, therefore strongly suggesting that
golysosome) for NLR ligands might direct the nature of improper targeting of bacteria by the autophagic machin-
the host response, such as NF-kB, caspase-1 inflamma- ery plays a key role in CD pathogenesis. The fact that
some or type I interferon pathways. This concept was bacteria could be targeted by Nod-dependent autophagy at
indeed recently put forward in the case of TLR stimu- the plasma membrane before cell invasion suggests that
lation, since the engagement of TLR4/MyD88/NF-kB these NLR proteins likely detect minute amounts of
versus TLR4/TRAM/type I interferon pathways were peptidoglycan delivered to the cytosol by the type III
found to occur at the level of the plasma membrane secretion system. Moreover, the rupturing of the mem-
versus early endosomes, respectively [44]. brane during bacterial invasion seems to provide a signaling
platform that potentially initializes both autophagy and
Induction of bacterial autophagy by Nod proteins NLR activation [45]. This illustrates another important
Autophagy is a cellular process through which defective role of Nod-dependent activation at host membranes. In
organelles, protein aggregates or foreign material agreement with these observations, Nod2-dependent
(including microbes) are sequestered into double mem- induction of autophagy in human dendritic cells has been
branes coated by proteins of the autophagic machinery, and shown to be critical for bacterial targeting to the lysosome
directed to lysosomes for destruction. Recently, the NLR and for subsequent optimal antigen presentation on the
major histocompatibility (MHC) complex II [46].
Figure 3
Concluding remarks
The functional importance of NLRs as cytosolic sentinels
of the innate immune system at the vicinity of host
membranes is an emerging concept that is supported
by numerous experimental evidence, as presented in this
review. Linking NLR activation to host membrane
patrolling likely confers two main advantages: (i) it allows
safe and rapid response to microbes and danger, since
cytosolic threats necessarily need to cross at least one host
membrane, and membrane rupture, damage or electro-
chemical alteration are common events triggered by
bacteria, viruses, parasites or danger signals. (ii) It allows
NLR activation in a restricted area of the cell where
signals to be detected (ROS, K+ efflux, microbial motifs
translocated through a specific secretion system, material
released from the lysosome) display their highest con-
centration, thus ensuring the activation threshold is effi-
ciently met. This last point likely explains how Nod1 can
induce innate immune response to extracellular bacterial
pathogens [47,48], or direct the recruitment of the autop-
hagic machinery at the site of bacterial entry, when
bacteria are still extracellular [6]. In the case of Helico-
bacter pylori, it was demonstrated that peptidoglycan is
translocated to the host cell cytosol via the type IV
Nod proteins trigger the recruitment of the autophagic machinery at the
bacterial entry site. (A) Nod proteins detect invading bacteria likely
secretion system, resulting in Nod1-dependent inflam-
following local delivery of peptidoglycan fragments. This results in the matory signaling [48].
recruitment of ATG16L1, which in turn directs the coalescence of the
autophagic machinery at the site of bacterial entry. (B) Schematic Finally, are there data to show NLR activation at sites
representation of the Nod1/2-dependent signaling cascade. While the
distant from host membranes? Paradoxically, for these
adaptor protein Rip2 is essential for Nod-dependent activation of NF-kB
as well as MAP kinase cascades, autophagy triggered by bacterial cytosolic sensors, direct evidence for this mode of acti-
invasion seems to operate in a Rip2-independent manner, likely through vation is lacking. Indeed, it remains unknown if for
the complex formed between Nod1/2 and ATG16L1. instance intracellular bacteria, moving freely in the host
Current Opinion in Immunology 2010, 22:428–434 www.sciencedirect.com
6. Sentinels at host membranes Philpott and Girardin 433
cytosol (as is the case for Shigella or Listeria), can be 16. Fukata M, Vamadevan AS, Abreu MT: Toll-like receptors (TLRs)
and Nod-like receptors (NLRs) in inflammatory disorders.
efficiently detected by NLRs, to trigger inflammatory Semin Immunol 2009, 21:242-253.
signaling or autophagy induction. Answering this crucial 17. Geddes K, Magalhaes JG, Girardin SE: Unleashing the
question will require the development of reactive probes therapeutic potential of NOD-like receptors. Nat Rev Drug
to allow visualization and measurement of NLR acti- Discov 2009, 8:465-479.
vation in live cells. 18. Park JH, Kim YG, McDonald C, Kanneganti TD, Hasegawa M,
Body-Malapel M, Inohara N, Nunez G: RICK/RIP2 mediates
innate immune responses induced through Nod1 and Nod2
Acknowledgements but not TLRs. J Immunol 2007, 178:2380-2386.
We apologize to those whose original work was not cited in this review,
because of space limitations. Research in the laboratories of D.J.P. and 19. Faustin B, Lartigue L, Bruey JM, Luciano F, Sergienko E,
Bailly-Maitre B, Volkmann N, Hanein D, Rouiller I, Reed JC:
S.E.G. is supported by funding from the Canadian Institutes of Health
Reconstituted NALP1 inflammasome reveals two-step
Research (to S.E.G. and D.J.P.), Crohn’s and Colitis Foundation of Canada mechanism of caspase-1 activation. Mol Cell 2007, 25:713-724.
(S.E.G.), Burrows Wellcome Fund (S.E.G.) and Howard Hughes Medical
Institutes (D.J.P.). 20. Barnich N, Aguirre JE, Reinecker HC, Xavier R, Podolsky DK:
Membrane recruitment of NOD2 in intestinal epithelial cells is
essential for nuclear factor-{kappa}B activation in muramyl
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