Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming

Elliott, Eric I.; Miller, Alexis N.; Banoth, Balaji; Iyer, Shankar S.; Stotland, Aleksandr; Weiss, Jerrold; Gottlieb, Roberta A.; Sutterwala, Fayyaz S.; Cassel, Suzanne L.

doi:10.4049/jimmunol.1701723

Cited by 114 publications

(136 citation statements)

References 21 publications

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“…NLRP3 is transported to the surface of mitochondria where these organelles then create ideal conditions for the exposure/presentation of triggers of NLRP3-ASC assembly, such as cardiolipin externalization. 104,105 Moreover, the contact areas between the ER and mitochondria have recently been identified as metabolic hubs 106 and, thus, could provide energetic support for the assembly of such macromolecular structures. With regard to complement, particularly the C1q receptor gC1qR/gp32, expressed on mitochondria, has an acknowledged history of impacting the activity of these organelles.…”

Section: Lo C Ati On Mat Ter S: S Patial B Ia S In Prr Ac Tivitie Smentioning

confidence: 99%

Complement and human T cell metabolism: Location, location, location

West

Kunz

Kemper

2020

Immunological Reviews

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Immunological Reviews. 2020;295:68-81. wileyonlinelibrary.com/journal/imr 1 | INTRODUC TI ON Our contemporary immune system has evolved under the constant pressure from a broad range of pathogens that manipulate the host to enhance their own propagation. As diverse as the pathogenic threats are, ranging from intra-and extracellular bacteria, viruses, fungi, and complex parasites, as elegant and effective are the defense mechanisms developed and employed by the host to combat this constant onslaught. Particularly, the detection systems that are functioning as the first lines of defense against such invaders are formidable. If a microbe has managed to penetrate the protective physical barriers, such as the skin, or lung, a range of innate immune sensors either circulating in the blood, lymph, and interstitial fluids or expressed in and on scavenger and sentinel cells, such as neutrophils and microphages, detect the conserved pathogen-associated molecular patterns (PAMPs). These sensor systems comprise several pattern recognition receptors (PRRs) and include the Toll-like receptors (TLRs), the NOD-like receptors (NLRs), the retinoic acid-inducible gene-I (RIG)-like system, several distinct inflammasomes, and the complement system-derived receptors. 1,2 Activation of PRRs by a pathogen is most often triggered in several sensor systems in parallel and then initiates the general inflammatory reaction as well as tailored immune cell activation specifically effective toward the identified pathogen. The ability of PRR systems to decisively discriminate between a real threat, that is non-self and dangerous self via recognizing so-called danger-associated molecular patterns (DAMPs), and self and harmless alterations of self is critical for our health. Thus, there are several checks and balances build into the PRR systems that prevent unwanted reactions against sensed AbstractThe complement system represents one of the evolutionary oldest arms of our immune system and is commonly recognized as a liver-derived and serum-active system critical for providing protection against invading pathogens. Recent unexpected findings, however, have defined novel and rather "uncommon" locations and activities of complement. Specifically, the discovery of an intracellularly active complement system-the complosome-and its key role in the regulation of cell metabolic pathways that underly normal human T cell responses have taught us that there is still much to be discovered about this system. Here, we summarize the current knowledge about the emerging functions of the complosome in T cell metabolism. We further place complosome activities among the non-canonical roles of other intracellular innate danger sensing systems and argue that a "location-centric" view of complement evolution could logically justify its close connection with the regulation of basic cell physiology. K E Y W O R D S CD46, complement, complosome, metabolism, T cells | 69 WEST ET al.innocuous antigens. However, PRRs not only take care to contain tissue injury during their...

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Section: Lo C Ati On Mat Ter S: S Patial B Ia S In Prr Ac Tivitie Smentioning

confidence: 99%

Complement and human T cell metabolism: Location, location, location

West

Kunz

Kemper

2020

Immunological Reviews

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“…#10), as knockdown of cardiolipin synthase attenuated NLRP3 activation . Nevertheless, it was recently suggested that mtROS generation at the inflammasome priming stage facilitates both NLRP3 and caspase‐1 association with cardiolipin on the outer mitochondria membrane, and thus cardiolipin may act as scaffolding for NLRP3 inflammasome assembly, rather than its activation . Notably, if the mitochondria acts as the inflammatory platform and trigger, it remains to be reconciled why in many studies the active inflammasome appears to be cytosolic, as evidenced by a lack of co‐localization of ASC specks with organelle markers …”

Section: Mechanisms For Nlrp3 Activationmentioning

confidence: 99%

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Yabal

Calleja

Simpson

et al. 2018

Journal of Leukocyte Biology

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Inflammasomes are multimeric protein complexes that induce the cleavage and release of bioactive IL-1 and cause a lytic form of cell death, termed pyroptosis. Due to its diverse triggers, ranging from infectious pathogens and host danger molecules to environmental irritants, the NOD-like receptor protein 3 (NLRP3) inflammasome remains the most widely studied inflammasome to date. Despite intense scrutiny, a universal mechanism for its activation remains elusive, although, recent research has focused on mitochondrial dysfunction or potassium (K + ) efflux as key events. In this review, we give a general overview of NLRP3 inflammasome activation and explore the recently emerging noncanonical and alternative pathways to NLRP3 activation. We highlight the role of the NLRP3 inflammasome in the pathogenesis of metabolic disease that is associated with mitochondrial and oxidative stress. Finally, we interrogate the mechanisms proposed to trigger NLRP3 inflammasome assembly and activation. A greater understanding of how NLRP3 inflammasome activation is triggered may reveal new therapeutic targets for the treatment of inflammatory disease. K E Y W O R D Scaspases, inflammasome, metabolism, mitochondria, reactive oxygen species Abbreviations: AIM2, absent in Melanoma; AMPK, AMP-activated protein kinase; APAF-1, apoptosis protease activating factor-1; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; BMDCs, bone marrow dendritic

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“…Next, we determined the site of Mul1-mediated poly-ubiquitination in Asc. For this aim, we generated ten KR single mutant Asc plasmids, in which each Lys residue (K21, 22,24,26,55,109,139,158,161, and 174) was replaced with Arg. When the wildtype (WT-) and mutant Asc plasmids were transfected into RAW264.7 cells that do not to express Asc [34], all Asc mutants were expressed to a similar extent ( Fig.…”

Section: Mul1 Reduces Asc Levels By K48-linked Poly-ubiquitination Anmentioning

confidence: 99%

“…Damaged mitochondria play a key role in inflammasome activation not only by generating harmful Nlrp3 activators including oxidized mitochondrial DNA [54] and reactive oxygen species [44], but also by acting as a platform for the Nlrp3 inflammasome assembly through binding of Nlrp3, Asc, and pro-caspase-1 to mitochondrial cardiolipin, which is externalized to the outer mitochondrial membrane at priming [55,56]. Hence, mitophagy is considered to be an important process for limiting the Nlrp3 inflammasome activation.…”

Section: Recently Barry Et Al Clearly Demonstrated That Nlrp3 Is Sumentioning

confidence: 99%

Mul1 suppresses Nlrp3 inflammasome activation through ubiquitination and degradation of Asc

Kim

Lee

Suh

2019

Preprint

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Activation of the Nlrp3 inflammasome consisting of three major components, Nlrp3, Asc, and pro-caspase-1, results in the activation of caspase-1 and subsequent proteolytic cleavage of pro-IL-1β and pro-IL-18. To avoid excessive inflammatory response, the Nlrp3 inflammasome has to be precisely controlled. In this study, we show that the mouse mitochondrial E3 ubiquitin protein ligase (Mul1) suppresses Nlrp3 inflammasome activation through ubiquitination and degradation of Asc. In J774A.1 cells, Mul1 overexpression attenuated Nlrp3 activation, whereas Mul1 knockdown augmented Nlrp3 activation in terms of IL-1β secretion and cleavage of pro-caspase-1 and pro-IL-1β. Mul1 interacted with Asc, and ubiquitinated it at K21, K22, K26, and K55 residues, in a K48-linked manner, leading to proteasomal degradation.Convincingly, Mul1-mediated suppression of Nlrp3 activation was inhibited by K21R-, K22R-, K26R-, K52R-Asc mutants in RAW264.7 cells, when compared with the wildtype Asc. Furthermore, Aim2 inflammasome activation was also inhibited by Mul1 in the wild-type Asc-, but not in mutant Asc-expressing RAW264.7 cells. Taken together, these data suggest that Mul1 suppresses Nlrp3 inflammasome activation, through Asc ubiquitination and degradation.

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Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming

Cited by 114 publications

References 21 publications

Complement and human T cell metabolism: Location, location, location

Complement and human T cell metabolism: Location, location, location

Stressing out the mitochondria: Mechanistic insights into NLRP3 inflammasome activation

Mul1 suppresses Nlrp3 inflammasome activation through ubiquitination and degradation of Asc

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