scholarly journals Sendai Virus V Protein Inhibits the Secretion of Interleukin-1β by Preventing NLRP3 Inflammasome Assembly

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Takayuki Komatsu ◽  
Yukie Tanaka ◽  
Yoshinori Kitagawa ◽  
Naoki Koide ◽  
Yoshikazu Naiki ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Sendai Virus ◽  
Nipah Virus ◽  
Innate Immune ◽  
Parainfluenza Virus ◽  
Inflammasome Activation ◽  
V Protein ◽  
Nlrp3 Inflammasome Activation ◽  
Human Parainfluenza Virus

ABSTRACT Inflammasomes play a key role in host innate immune responses to viral infection by caspase-1 (Casp-1) activation to facilitate interleukin-1β (IL-1β) secretion, which contributes to the host antiviral defense. The NLRP3 inflammasome consists of the cytoplasmic sensor molecule NLRP3, adaptor protein ASC, and effector protein pro-caspase-1 (pro-Casp-1). NLRP3 and ASC promote pro-Casp-1 cleavage, leading to IL-1β maturation and secretion. However, as a countermeasure, viral pathogens have evolved virulence factors to antagonize inflammasome pathways. Here we report that V gene knockout Sendai virus [SeV V(−)] induced markedly greater amounts of IL-1β than wild-type SeV in infected THP1 macrophages. Deficiency of NLRP3 in cells inhibited SeV V(−)-induced IL-1β secretion, indicating an essential role for NLRP3 in SeV V(−)-induced IL-1β activation. Moreover, SeV V protein inhibited the assembly of NLRP3 inflammasomes, including NLRP3-dependent ASC oligomerization, NLRP3-ASC association, NLRP3 self-oligomerization, and intermolecular interactions between NLRP3 molecules. Furthermore, a high correlation between the NLRP3-binding capacity of V protein and the ability to block inflammasome complex assembly was observed. Therefore, SeV V protein likely inhibits NLRP3 self-oligomerization by interacting with NLRP3 and inhibiting subsequent recruitment of ASC to block NLRP3-dependent ASC oligomerization, in turn blocking full activation of the NLRP3 inflammasome and thus blocking IL-1β secretion. Notably, the inhibitory action of SeV V protein on NLRP3 inflammasome activation is shared by other paramyxovirus V proteins, such as Nipah virus and human parainfluenza virus type 2. We thus reveal a mechanism by which paramyxovirus inhibits inflammatory responses by inhibiting NLRP3 inflammasome complex assembly and IL-1β activation. IMPORTANCE The present study demonstrates that the V protein of SeV, Nipah virus, and human parainfluenza virus type 2 interacts with NLRP3 to inhibit NLRP3 inflammasome activation, potentially suggesting a novel strategy by which viruses evade the host innate immune response. As all members of the Paramyxovirinae subfamily carry similar V genes, this new finding may also lead to identification of novel therapeutic targets for paramyxovirus infection and related diseases.

scholarly journals The NLRP3 Inflammasome as a Novel Player of the Intercellular Crosstalk in Metabolic Disorders

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Elisa Benetti ◽  
Fausto Chiazza ◽  
Nimesh S. A. Patel ◽  
Massimo Collino
Keyword(s):  
Chronic Inflammation ◽  
Nlrp3 Inflammasome ◽  
Metabolic Disorders ◽  
Inflammasome Activation ◽  
Nucleotide Binding Domain ◽  
Metabolic Inflammation ◽  
Nlrp3 Inflammasome Activation ◽  
Leucine Rich Repeat Protein

The combination of obesity and type 2 diabetes is a serious health problem, which is projected to afflict 300 million people worldwide by 2020. Both clinical and translational laboratory studies have demonstrated that chronic inflammation is associated with obesity and obesity-related conditions such as insulin resistance. However, the precise etiopathogenetic mechanisms linking obesity to diabetes remain to be elucidated, and the pathways that mediate this phenomenon are not fully characterized. One of the most recently identified signaling pathways, whose activation seems to affect many metabolic disorders, is the “inflammasome,” a multiprotein complex composed of NLRP3 (nucleotide-binding domain and leucine-rich repeat protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and procaspase-1. NLRP3 inflammasome activation leads to the processing and secretion of the proinflammatory cytokines interleukin- (IL-) 1βand IL-18. The goal of this paper is to review new insights on the effects of the NLRP3 inflammasome activation in the complex mechanisms of crosstalk between different organs, for a better understanding of the role of chronic inflammation in metabolic disease pathogenesis. We will provide here a perspective on the current research on NLRP3 inflammasome, which may represent an innovative therapeutic target to reverse the detrimental metabolic consequences of the metabolic inflammation.

scholarly journals The conserved carboxyl terminus of human parainfluenza virus type 2 V protein plays an important role in virus growth

Virology ◽  
2007 ◽  
Vol 362 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Machiko Nishio ◽  
Masato Tsurudome ◽  
Hisamitsu Ishihara ◽  
Morihiro Ito ◽  
Yasuhiko Ito
Keyword(s):  
Virus Type ◽  
Parainfluenza Virus ◽  
Carboxyl Terminus ◽  
Virus Growth ◽  
V Protein ◽  
Human Parainfluenza Virus

Protein Tyrosine Phosphatase Non-Receptor Type 2 Regulates NLRP3 Inflammasome Activation

2011 ◽  
Vol 140 (5) ◽  
pp. S-633
Author(s):  
Helen M. Becker ◽  
Barbara Schnell ◽  
Joba M. Arikkat ◽  
Markus Schuppler ◽  
Martin J. Loessner ◽  
...  
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Nlrp3 Inflammasome ◽  
Tyrosine Phosphatase ◽  
Receptor Type ◽  
Inflammasome Activation ◽  
Protein Tyrosine ◽  
Nlrp3 Inflammasome Activation

scholarly journals Human Parainfluenza Virus Type 2 V Protein Inhibits Genome Replication by Binding to the L Protein: Possible Role in Promoting Viral Fitness

2008 ◽  
Vol 82 (13) ◽  
pp. 6130-6138 ◽  
Author(s):  
Machiko Nishio ◽  
Junpei Ohtsuka ◽  
Masato Tsurudome ◽  
Tetsuya Nosaka ◽  
Daniel Kolakofsky
Keyword(s):  
Virus Type ◽  
Viral Fitness ◽  
Parainfluenza Virus ◽  
Genome Replication ◽  
Gfp Expression ◽  
Virus Growth ◽  
V Protein ◽  
L Protein ◽  
Human Parainfluenza Virus

ABSTRACT The human parainfluenza virus type 2 (hPIV2) V protein plays important roles in inhibiting the host interferon response and promoting virus growth, but its role in hPIV2 replication and transcription is not clear. A green fluorescent protein (GFP)-expressing a negative-sense minigenomic construct of hPIV2 has been established by standard technology, with helper plasmids expressing the nucleocapsid protein (NP), phosphoprotein (P), and large RNA polymerase (L) protein, to examine the role of V protein. We found that the simultaneous expression of wild-type V protein in the minigenome system inhibited GFP expression, at least in part, by inhibiting minigenome replication. In contrast, expression of C terminally truncated or mutant hPIV2 V proteins had no effect. Moreover, the V protein of simian virus 41, the rubulavirus most closely related virus to hPIV2, also inhibited GFP expression, whereas that of PIV5, a more distantly related rubulavirus, did not. Using these other rubulavirus V proteins, as well as various mutant hPIV2 V proteins, we found that the ability of V protein to inhibit GFP expression correlated with its ability to bind to L protein via its C-terminal V protein-specific region, but there was no correlation with NP binding. A possible role for this inhibition of genome replication in promoting viral fitness is discussed.

scholarly journals Degradation of STAT1 and STAT2 by the V Proteins of Simian Virus 5 and Human Parainfluenza Virus Type 2, Respectively: Consequences for Virus Replication in the Presence of Alpha/Beta and Gamma Interferons

2002 ◽  
Vol 76 (5) ◽  
pp. 2159-2167 ◽  
Author(s):  
J. Andrejeva ◽  
D. F. Young ◽  
S. Goodbourn ◽  
R. E. Randall
Keyword(s):  
Protein Synthesis ◽  
Cell Lines ◽  
Simian Virus ◽  
Parainfluenza Virus ◽  
V Protein ◽  
Simian Virus 5 ◽  
Ifn Γ ◽  
Alpha Beta ◽  
Human Parainfluenza Virus

ABSTRACT Human cell lines were isolated that express the V protein of either simian virus 5 (SV5) or human parainfluenza virus type 2 (hPIV2); the cell lines were termed 2f/SV5-V and 2f/PIV2-V, respectively. STAT1 was not detectable in 2f/SV5-V cells, and the cells failed to signal in response to either alpha/beta interferons (IFN-α and IFN-β, or IFN-α/β) or gamma interferon (IFN-γ). In contrast, STAT2 was absent from 2f/PIV2-V cells, and IFN-α/β but not IFN-γ signaling was blocked in these cells. Treatment of both 2f/SV5-V and 2f/PIV2-V cells with a proteasome inhibitor allowed the respective STAT levels to accumulate at rates similar to those seen in 2fTGH cells, indicating that the V proteins target the STATs for proteasomal degradation. Infection with SV5 can lead to a complete loss of both phosphorylated and nonphosphorylated forms of STAT1 by 6 h postinfection. Since the turnover of STAT1 in uninfected cells is longer than 24 h, we conclude that degradation of STAT1 is the main mechanism by which SV5 blocks interferon (IFN) signaling. Pretreatment of 2fTGH cells with IFN-α severely inhibited both SV5 and hPIV2 protein synthesis. However, and in marked contrast, pretreatment of 2fTGH cells with IFN-γ had little obvious effect on SV5 protein synthesis but did significantly reduce the replication of hPIV2. Pretreament with IFN-α or IFN-γ did not induce an antiviral state in 2f/SV5-V cells, indicating either that the induction of an antiviral state is completely dependent on STAT signaling or that the V protein interferes with other, STAT-independent cell signaling pathways that may be induced by IFNs. Even though SV5 blocked IFN signaling, the addition of exogenous IFN-α to the culture medium of 2fTGH cells 12 h after a low-multiplicity infection with SV5 significantly reduced the subsequent cell-to-cell spread of virus. The significance of the results in terms of the strategy that these viruses have evolved to circumvent the IFN response is discussed.

scholarly journals NLRP3 Inflammasome in Diabetic Cardiomyopathy and Exercise Intervention

2021 ◽  
Vol 22 (24) ◽  
pp. 13228
Author(s):  
Yi Sun ◽  
Shuzhe Ding
Keyword(s):  
Diabetic Cardiomyopathy ◽  
Nlrp3 Inflammasome ◽  
Exercise Intervention ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Low Grade ◽  
Chronic Exercise ◽  
Nlrp3 Inflammasome Activation ◽  
Low Grade Inflammation

Diabetic cardiomyopathy (DCM), as a common complication of diabetes, is characterized by chronic low-grade inflammation. The NLRP3 inflammasome is a key sensor mediating innate immune and inflammatory responses. However, the mechanisms initiating and promoting NLRP3 inflammasome activation in DCM is largely unexplored. The aim of the present review is to describe the link between NLRP3 inflammasome and DCM, and to provide evidence highlighting the importance of exercise training in DCM intervention. Collectively, this evidence suggests that DCM is an inflammatory disease aggravated by NLRP3 inflammasome-mediated release of IL-1β and IL-18. In addition, chronic exercise intervention is an effective preventive and therapeutic method to alleviate DCM via modulating the NLRP3 inflammasome.

scholarly journals The V protein of human parainfluenza virus type 2 promotes RhoA-induced filamentous actin formation

Virology ◽  
2018 ◽  
Vol 524 ◽  
pp. 90-96 ◽  
Author(s):  
Keisuke Ohta ◽  
Yusuke Matsumoto ◽  
Natsuko Yumine ◽  
Machiko Nishio
Keyword(s):  
Virus Type ◽  
Parainfluenza Virus ◽  
Filamentous Actin ◽  
V Protein ◽  
Human Parainfluenza Virus

Increasing Autophagy ameliorate all-trans-retinal-activated NLRP3 Inflammasome 2 in human THP-1 macrophage cells

2021 ◽  
Author(s):  
Qingqing Xia ◽  
Lvxing Huang ◽  
Hengyi Chen ◽  
Yingying Zhou ◽  
Lingmin Zhang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Underlying Mechanism ◽  
Innate Immune ◽  
Cell Counting ◽  
Autophagic Flux ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Related Proteins ◽  
Excessive Activation ◽  
Insight Into

Abstract BackgroundProfound inflammation that mediated by innate immune sensors can be observed in retina, and is considered to play an important role in the pathogenesis of all-trans-retinal (atRAL)-caused retinal degeneration. However, the underlying mechanism remains elusive. MethodsCell viability was detected with Cell Counting Kit-8 (CCK-8). The concentration of IL-1β was evaluated using IL-1β ELISA Kits. The levels of autophagy-related proteins were measured by Western blotting. The measurement of autophagic flux was performed with virus vectors packing tandem monomeric mCherry-eGFP-tagged LC3B. ResultsWe focused on studying the effects of atRAL on macrophage cell line THP-1 and determining the underlying signal pathway through pharmacological and genetical manipulation. We first found the maturation and release of IL-1β was regulated by the activation of NLRP3 inflammasome. We secondly found that mitochondria-associated reactive oxygen species (ROS) were involved in the regulation of NLRP3 inflammasome activation and caspase 1 cleavage. Finally, we found that atRAL functionally activated autophagy in THP-1 cells, and atRAL-caused NLRP3 inflammasome activation is suppressed by autophagy. Overall, our results show atRAL simultaneously activates NLRP3 inflammasome and autophagy in THP-1 cells, and increasing autophagy leads to the inhibition of the excessive activation of NLRP3 inflammasome. Our study provides new insight into the pathogenesis of aging related retina degeneration.

scholarly journals Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders

2017 ◽  
Vol 214 (11) ◽  
pp. 3219-3238 ◽  
Author(s):  
Hua Jiang ◽  
Hongbin He ◽  
Yun Chen ◽  
Wei Huang ◽  
Jinbo Cheng ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Ex Vivo ◽  
Binding Motif ◽  
Inflammasome Activation ◽  
Therapeutic Effects ◽  
Nlrp3 Inflammasome Activation ◽  
Molecule Inhibitor ◽  
Synovial Fluid Cells

The NLRP3 inflammasome has been implicated in the pathogenesis of a wide variety of human diseases. A few compounds have been developed to inhibit NLRP3 inflammasome activation, but compounds directly and specifically targeting NLRP3 are still not available, so it is unclear whether NLRP3 itself can be targeted to prevent or treat diseases. Here we show that the compound CY-09 specifically blocks NLRP3 inflammasome activation. CY-09 directly binds to the ATP-binding motif of NLRP3 NACHT domain and inhibits NLRP3 ATPase activity, resulting in the suppression of NLRP3 inflammasome assembly and activation. Importantly, treatment with CY-09 shows remarkable therapeutic effects on mouse models of cryopyrin-associated autoinflammatory syndrome (CAPS) and type 2 diabetes. Furthermore, CY-09 is active ex vivo for monocytes from healthy individuals or synovial fluid cells from patients with gout. Thus, our results provide a selective and direct small-molecule inhibitor for NLRP3 and indicate that NLRP3 can be targeted in vivo to combat NLRP3-driven diseases.

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