Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation

Romberg, Neil; Moussawi, Khatoun Al; Nelson‐Williams, Carol; Stiegler, Amy L.; Loring, Erin; Choi, Murim; Overton, John D.; Meffre, Eric; Khokha, Mustafa K.; Hüttner, Anita; West, Brian; Podoltsev, Nikolai A.; Boggon, Titus J.; Kazmierczak, Barbara I.; Lifton, Richard P.

doi:10.1038/ng.3066

Cited by 455 publications

(413 citation statements)

References 28 publications

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“…Recently, activating mutations in the gene coding for another NLR, NLRC4, have been associated with an autoinflammatory disease that differs from CAPS [52,53]. Patients with these NLRC4 mutations exhibited early-onset spontaneous fevers, gastrointestinal (GI) inflammation, urticaria, splenomegaly and malaise.…”

Section: Autoinflamamatory Diseases Linked To Disorders In Protein MImentioning

confidence: 99%

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Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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Section: Autoinflamamatory Diseases Linked To Disorders In Protein MImentioning

confidence: 99%

“…In contrast to CAPS but like MAS, monocytes and macrophages with the NLRC4 mutations showed hypersecretion of IL-18 [52]. Romberg et al showed that NLRC4 mutant macrophages also exhibited increased apoptosis [53].…”

Section: Autoinflamamatory Diseases Linked To Disorders In Protein MImentioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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“…5). V341A and T337S patients had very high serum IL-18 levels compared to healthy volunteers or CAPS patients [72,73].…”

Section: Nlrp3 Is Recruited To the Same Complex As Phosphorylation Dementioning

confidence: 99%

“…The V341A mutation causes severe inflammatory phenotype in humans, with neonatal-onset enterocolitis [72], while T337S mutation leads to early-onset recurrent fever flares and macrophage activation syndrome [73]. These mutants are active in the absence of known NLRC4 activators (Fig.…”

Section: Nlrp3 Is Recruited To the Same Complex As Phosphorylation Dementioning

confidence: 99%

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

Hafner-Bratkovič¹

2017

Inflammasome

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Inflammasomes are intracellular multiprotein platforms for the activation of inflammatory caspases. As components of the innate immune system, they play an important role in the fight against microbes. However, aberrant inflammasome activation has been implicated in auto-inflammatory syndromes. This review focuses on the NLRC4 inflammasome. This is perhaps not the most extensively studied, yet its mechanism of activation is by far the best understood. The NLRC4 inflammasome is activated by several proteins originating from intracellular bacteria, which are first sensed by receptors of the NAIP family. Activated NAIP binds NLRC4, which further recruits dormant NLRC4 molecules in a prion-like oligomerization event. NLRC4 enables a strong amplification of the signal, providing a fast and robust host response. The review also discusses peculiar NLRC4 inflammasome functions in promoting eicosanoid biosynthesis, actin reorganization, and its roles in autoinflammatory syndromes and sterile inflammation. Finally, the first inflammasomeindependent engagement of NLRC4 in suppressing melanoma tumor growth is presented. The emerging roles of NLRC4 in various normal and pathological processes demonstrate that there is still plenty to be learned about the NLRC4 mechanism of activation and downstream functions.

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“…A matching receptor surface is preformed in the inactive NLRC4 molecule, and mediates the recruitment of NLRC4 into the growing complex. Intriguingly, missense mutations in NLRC4 that are associated with autoinflammatory conditions map to this important hinge region [7][8][9]. Whether such mutations induce the formation of NLRC4 disks in the absence of activated NAIPs remains to be shown, but the new studies provide the structural basis for understanding these gain-of-function mutations.…”

mentioning

confidence: 99%

Inflammasome assembly: The wheels are turning

Brož

2015

Cell Res

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Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation

Cited by 455 publications

References 28 publications

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

The NLRC4 inflammasome: The pieces of the puzzle are falling into place

Inflammasome assembly: The wheels are turning

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