The CATERPILLER Protein Monarch-1 Is an Antagonist of Toll-like Receptor-, Tumor Necrosis Factor α-, and Mycobacterium tuberculosis-induced Pro-inflammatory Signals

Williams, Kristi; Lich, John D.; Duncan, Joseph A.; Reed, William; Rallabhandi, Prasad; Moore, Christopher; Kurtz, Sherry L.; Coffield, Vernon M.; Accavitti-Loper, Mary Ann; Su, Lishan; Vogel, Stefanie N.; Braunstein, Miriam; Ting, Jenny P.‐Y.

doi:10.1074/jbc.m502820200

Cited by 200 publications

(257 citation statements)

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“…In THP-1 cells, silencing Monarch-1 causes a dramatic enhancement of NF-κB activation upon TLR stimulation, suggesting that endogenous Monarch-1 functions as a negative regulator of the NF-κB response in monocytes. Furthermore, the production of the proinflammatory cytokines IL-6 and IL-1β is elevated in Monarch-1 silenced THP-1 monocytes in response to TLR4 agonists (LPS), TLR2 agonists (Pam3Cys) or whole bacteria (M. tuberculosis) [18]. This negative regulatory role was confirmed in reciprocal experiments utilizing THP-1 cells stably expressing elevated levels of Monarch-1.…”

Section: Monarch-1 Functionmentioning

confidence: 73%

“…Our studies have led to the finding that Monarch-1 intersects the TLR signaling pathway through its association with IRAK1 [18]. The association with IRAK1 is mediated through the NBD of Monarch-1 and is induced following TLR stimulation.…”

Section: Toward Identifying the Molecular Mechanisms Of Monarch-1 Actmentioning

confidence: 89%

“…This myeloid restricted pattern of expression provided the initial clue that the protein may be a regulator of the immune response, inflammation and host response to pathogens. In examining the mRNA expression, we found that Monarch-1 expression is reduced by greater than 65-80% after an 1 h treatment with purified E. coli LPS, which activates TLR4, or peptidoglycan/Pam3Cys, which activates TLR2 [18]. Similarly, live bacteria including M. tuberculosis and P. gingivalis all resulted in reduced Monarch-1.…”

Section: Monarch-1 Expressionmentioning

confidence: 94%

“…This response in Monarch-1 expression is not limited to TLRs. Indeed, expression is also down-regulated upon exposure of PBMC to TNFα or IFNγ [18]. These results, coupled with the functional studies to be reviewed below, have led to hypothesis that Monarch-1 functions as a negative regulator of inflammatory responses induced by TLRs and cytokines.…”

Section: Monarch-1 Expressionmentioning

confidence: 96%

“…Monarch-1 functions as a negative regulator of inflammation by suppressing the production of proinflammatory cytokines and chemokines [18]. Based on reporter gene assays, Monarch-1 exerts this anti-inflammatory function by inhibiting NF-κB activation.…”

Section: Toward Identifying the Molecular Mechanisms Of Monarch-1 Actmentioning

confidence: 99%

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Monarch-1/PYPAF7 and other CATERPILLER (CLR, NOD, NLR) proteins with negative regulatory functions

Lich

Ting

2007

Microbes and Infection

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CATERPILLER is a mammalian gene family with signature NBD and LRR domains. Several members of this family are positive regulators of inflammatory responses. Others, however, exert negative effects on proinflammatory responses. These data are particularly convincing when shRNA/ siRNA are used. This review focuses on the Monarch-1/PYPAF7 gene with brief discussions of CLR16.2/NOD3, PYPAF2/PAN1/NALP2, and PYPAF3.

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Section: Monarch-1 Functionmentioning

confidence: 73%

Section: Toward Identifying the Molecular Mechanisms Of Monarch-1 Actmentioning

confidence: 89%

Section: Monarch-1 Expressionmentioning

confidence: 94%

Section: Monarch-1 Expressionmentioning

confidence: 96%

Section: Toward Identifying the Molecular Mechanisms Of Monarch-1 Actmentioning

confidence: 99%

See 3 more Smart Citations

Monarch-1/PYPAF7 and other CATERPILLER (CLR, NOD, NLR) proteins with negative regulatory functions

Lich

Ting

2007

Microbes and Infection

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NOD‐Like Receptors

Arnold

Kienes

Sowa

et al. 2018

Encyclopedia of Life Sciences

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NOD‐like receptors (NLRs) are a family of pattern recognition receptors (PRRs), able to respond to conserved microbial structures and endogenous danger signals. NLRs modulate the inflammatory response via multiple pathways including NFκB (nuclear factor kappa‐light chain‐enhancer of activated B cells)‐activation, MAPKs, ERK and inflammasome formation, which results in IL‐1β release. They act in synergy with other PRRs, bridging innate to adaptive immunity. Moreover, some NLRs directly modulate adaptive immunity via transcriptional regulation of MHC (major histocompatibility complex) class I and class II. Their essential role in orchestrating inflammatory responses is seen via their association with morbidity. NLR dysfunction can result in cancer and autoinflammatory diseases, such as Crohn's disease and ulcerative colitis, pointing out their important role in maintaining gut homeostasis. Key Concepts NLRs are an intracellular subclass of PRRs that recognise microbe‐associated molecular patterns (MAMPs) and danger‐associated molecular patterns (DAMPs). NLRs are found in different animal species and have homologues in plants. NLRs share a common tripartite structure, typically consisting of an N ‐terminal domain from the death‐fold family, a central NACHT domain and a variable number of C ‐terminal LRRs. Activation of NLRs primes innate and adaptive immunity and drives the expression of MHC class I and class II genes. Some NLRs form inflammasomes, multiprotein platforms for caspase‐1 activation and IL‐1β release. NLRs maintain gut homeostasis, differentiating between commensals and pathogens. Mutations in NLRs can lead to severe autoinflammatory diseases, cancer, dysregulation of gut homeostasis and innate immune responses. Evidence suggests that some NLRs are further implicated in development. The function of some of the 22 human NLR proteins remains elusive.

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Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation

Borghini

Tassi²,

Chiesa

et al. 2011

Arthritis & Rheumatism

171

119

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ObjectiveNLRP12 mutations have been described in patients affected with peculiar autoinflammatory symptoms. This study was undertaken to characterize NLRP12 mutations in patients with autoinflammatory syndromes, particularly a novel missense mutation, p.D294E, affecting a protein sequence crucial for ATP binding, which was identified in a Caucasian family with familial cold-induced autoinflammatory syndrome in some family members.MethodsFifty patients were tested for NLRP12 mutations. A Caucasian family with the p.D294E missense mutation of NLRP12 in some family members was clinically characterized. In vitro analysis of the effects of the mutation on NF-κB activity was performed in HEK 293 cells after cotransfection of the cells with a luciferase NF-κB–responsive element and mutant or wild-type (WT) NLRP12 expression plasmids. NF-κB activity was also evaluated 24 hours after stimulation with tumor necrosis factor α in monocytes from individual family members carrying the mutation. Furthermore, secretion of interleukin-1β (IL-1β), production of reactive oxygen species (ROS), and activation of antioxidant systems in patient and healthy donor monocytes, under resting conditions and after stimulation with pathogen-associated molecular patterns (PAMPs), were also assessed.ResultsIn the family assessed, the p.D294E mutation segregated in association with a particular sensitivity to cold exposure (especially arthralgias and myalgia), but not always with an inflammatory phenotype (e.g., urticarial rash or fever). In vitro, the mutant protein maintained the same inhibitory activity as that shown by WT NLRP12. Consistently, NLRP12-mutated monocytes showed neither increased levels of p65-induced NF-κB activity nor higher secretion of IL-1β. However, the kinetics of PAMP-induced IL-1β secretion were significantly accelerated, and high production of ROS and up-regulation of antioxidant systems were demonstrated.ConclusionEven with a variable range of associated manifestations, the extreme sensitivity to cold represents the main clinical hallmark in an individual carrying the p.D294E mutation of the NLRP12 gene. Although regulation of NF-κB activity is not affected in patients, redox alterations and accelerated secretion of IL-1β are associated with this mild autoinflammatory phenotype.

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The CATERPILLER Protein Monarch-1 Is an Antagonist of Toll-like Receptor-, Tumor Necrosis Factor α-, and Mycobacterium tuberculosis-induced Pro-inflammatory Signals

Cited by 200 publications

References 53 publications

Monarch-1/PYPAF7 and other CATERPILLER (CLR, NOD, NLR) proteins with negative regulatory functions

Monarch-1/PYPAF7 and other CATERPILLER (CLR, NOD, NLR) proteins with negative regulatory functions

NOD‐Like Receptors

Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation

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