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Source—“Sister of the Logical Scripture Science“ Lanhan Life Sciences" Written by Maki Editor- Wang Sizhen ， Edited by Binwei Yang, Sizhen
Wang The inflammasome is a multi-protein polymeric complex that plays a key role in the innate immune response caused by pathogen invasion or tissue damage [1-4].
Classical inflammasome are composed of
pattern recognition receptors, effector protein Caspase1, and scaffold protein ASC.
These pattern-recognition receptors include members of the Nod-like receptors family and AIM2-like receptors Family members and Pyrin, among others
.
After being activated, the pattern recognition receptor is multipolymerized, and then ASC and Caspase1 enzymes are recruited to assemble into inflammasomes, which in turn activate Caspase1
.
The activated Caspase1 on the one hand shears the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18).
Precursors promote their maturation and release; On the other hand, activated Caspase1 shears Gasdermin D to release its N-segment active fragment, which punches holes in the cell membrane and initiates lytic cell death, also known as cytopyrosis ( Pyroptosis）[1-4]
。
Different inflammasome can be activated by specific mechanisms, and most of the pattern recognition receptors of inflammosomes can recognize a certain type or class of stimuli
.
However, NLRP3 (NLR family pyrin domain-containing protein 3) inflammasome is a special case because it can be activated by a wide range of stimuli, including extracellular ATP and bacterial toxins.
poorly soluble particles and pathogenic microorganisms, etc
.
It is generally believed that the activation of NLRP3 inflammasome requires two signaling steps, namely preprocessing and activation
.
Pretreatment signals can be obtained by toll-like receptor or cytokine receptor activation, which activates the NF-κB signaling pathway to promote the transcription and translation of NLRP3 and cytokines, and may also cause NLRP3 changes in post-translational modifications; Activation signals are mediated by the aforementioned stimuli to trigger the assembly of inflammosomes [4].
Depending on the properties of these stimuli, a number of different mechanisms have been proposed to mediate the activation and assembly of NLRP3 inflammasomes [4].
Most stimulants activate the NLRP3 inflammasome by triggering intracellular potassium efflux [5].
However, the molecular mechanism of NLRP3 recognition induction remains a mystery, and it is a long-standing biological problem
in the field.
On November 28, 2022, Zhang Zhironghe from the French Institute of Genetics, Molecular Cell Biology (IGBMC).
The Romeo RICCI team worked with the Antonella de Matteis team from the Telethon Institute of Genetics and Medicine (TIGEM) in Italy Nature Immunology published "Distinct changes in endosomal composition promote NLRP3 inflammasome activation" online The article reveals the cellular biological mechanism of NLRP3 inflammasome activation: NLRP3 activation occurs on endosomes, and NLRP3 can sense changes in its components under endosomal stress
.
It was previously reported that NLRP3 could be recruited to be rich in PI4P (Phosphatidylinositol 4-phosphate) and this process is important for its activation [6].
。 By resolving the biological properties of this vesicle, the study authors found that NLRP3-positive vesicles carry marker molecules for early endosomes, including EEA1 , RAB5 and SNX2
.
In experiments to label early endocytosomes by transferring in loading, the authors also observed that NLRP3 was recruited to be rich in both PI4P and Transferrin of early endocytosis
.
NLRP3 is activated after recruitment to early endocytosomes and is able to initiate the assembly
of inflammasomes.
These results suggest that activation of NLRP3 occurs on early endosomes, rather than on vesicles derived from trans-Golgi networks (TGNs) previously reported [6].
。 By regulating the kinase PI4Ks (Phosphatidylinositol 4-kinases) responsible for PI4P synthesis and responsible for PI4P The authors further confirmed that PI4P plays a key role in NLRP3 activation on endosomes, rather than on TGN-derived vesicles (Figure 1).
Figure 1 Activation of NLRP3 occurs on endosomes (Source: Zhang Z, et al.
, Nat Immunol, 2022).
Why is PI4P enriched on endosomes? In the course of further research, the authors were surprised to find that NLRP3 activators can destroy the endosome-ER contact site (EECS).
This leads to the enrichment
of PI4P on endosomes.
This phenomenon is consistent with previous reports that EECS plays a crucial role in the fine regulation of PI4P levels on endosomes [7,8].
HeLa cells with POPs (VAPA and VAPB) anchored in endoplasmic reticulum or PI4P transfer protein OSBP on endosomal bodies (without expressing ASC), PI4P is abundant on endosomes, and NLRP3 can be spontaneously recruited onto
endosomes.
At the same time, after knocking out VAPs or OSBPs in THP-1 cells, the authors found that these cells were able to activate with only LPS pretreatment NLRP3 inflammasomes
.
These results suggest that NLRP3 activators promote NLRP3 by disrupting EECS leading to the enrichment of PI4P on endosomes is recruited onto endosomes and initiates inflammasome activation and assembly (Figure 2).
Figure 2 NLRP3 activator disrupts EECS, resulting in PI4P enrichment on endosomes and activation of inflammosome assembly (Source: Zhang Z, et al.
, Nat Immunol, 2022)
Figure 3 NLRP3 activates blocking ET, resulting in Blockade of TGN cargoes in endosomes (Source: Zhang Z, et al.
, Nat Immunol, 2022).
It has been shown that the enrichment of PI4P on endosomes disrupts the normal division of endosomes (fission) and cargo sorting, thereby affecting the transport of TGN-targeting cargo from endosomes to TGN ( Endosome-to-TGN trafficking，ETT）
。 Such cargo includes TGN46 for cyclic transport between cell membranes-endocytosomes.
Thus, the authors tracked the sublocalization
of TGN46 in cells stimulated by NLRP3 activators.
The experimental results showed that in < B211> Stimulated by NLRP3 activator, the cell sublocalization of TGN46 was altered and localized on
NLRP3-positive endocytosomes.
This phenomenon suggests that TGN46 transport from endosomes to TGN may be blocked (Figure 3).
By tracking Shiga-like toxin and another TGN cargo, CI-MPR, to transport in cells under the same conditions, the authors further demonstrated that NLRP3 activators can block endosomes Transportation of TGN, resulting in detention on endocytosis of cargo targeting TGN, including TGN46 (Figure 4)
。 The authors also looked at TGN-labeled molecules GCC1/GCC88, GCC2/GCC185, and Golgin97 containing the GRIP domain and Golgin245/p230 for cell sublocalization under the same stimulation conditions, and the experimental results showed that there was no significant change
in the sublocalization of these molecules in cells stimulated by NLRP3 activator.
Since the localization of these marker molecules on TGN is not dependent on ETT, the possibility of TGN dissolution proposed by previous studies is ruled out [6].
Figure 4: Blocking ETT can promote the activation of NLRP3 inflammasome (Source: Zhang Z, et al.
, Nat Immunol, 2022)
Finally, the authors further reveal that ETT blocking is not just NLRP3 Activator stimulation is a side effect caused by active participation in the activation process
of NLRP3.
In ETT-deficient cells, the authors observed phenomena similar to those observed in VAPs or OSBP-deficient cells, i.
e.
, PI4P enrichment and sums on endosomes NLRP3 is spontaneously recruited onto endosomes and activated
.
In addition, mice with myeloid cell EET deletion were more sensitive to LPS-induced endotoxemia, and this was mainly caused
by hyperactivation of NLRP3 inflammasomes.
Figure 5 A new model of NLRP3 induction recognition mechanism (Source: Zhang Z, et al.
, Nat Immunol, 2022).
In summary, this research work reveals that the activation of NLRP3 inflammasome occurs on endophasomes, which is the future NLRP3 The study of inflammasome provides new guidance (Figure 5); At the same time, the detailed molecular mechanism of impaired endosomal function caused by NLRP3 activators was elucidated.
A new model of NLRP3 induction recognition - NLRP3 induction recognizes changes in specific components of endosomes under stress (Figure 5).
。 The study also raises new questions to be further addressed: 1) How do NLRP3 activators disrupt EECS? 2) Although PI4P on endosomes is important for the activation of NLRP3 inflammasomes, are there other endosome-related factors involved in this process? In addition, do other types of NLRP3 activators, such as poorly soluble particulate matter and pathogenic microorganisms, also activate NLRP3 inflammasome through this molecular mechanism?
Original link: style="font-size: 12px;color: rgb(172, 57, 255);" _mstmutation="1" _istranslated="1">
Corresponding authors: Zhang Zhirong (left), Romeo Ricci (middle), Antonella De Matteis (right).
(Photo courtesy of Zhang Zhirong/Romeo Ricci/Antonella De Matteis)
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Recruitment—"Logical Neuroscience" Recruitment Article Interpretation/Writing Position ( Online Part-time, Online Office) References (swipe up and down to read).
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et al.
K+efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter.
Immunity 38, 1142–1153 (2013).
6.
Chen, J.
& Chen, Z.
J.
PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation.
Nature 564, 71–76 (2018).
7.
Dong, R.
et al.
Endosome-ER Contacts Control Actin Nucleation and Retromer Function through VAP-Dependent Regulation of PI4P.
Cell 166, 408–423 (2016).
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& Voeltz, G.
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