Zika virus infection induces host inflammatory responses by facilitating NLRP3 inflammasome assembly and interleukin-1β secretion

Wang, Wenbiao; Li, Geng; Wu, De; Luo, Zhen; Pan, Pan; Tian, Mingfu; Wang, Yingchong; Xiao, Feng; Li, Aixin; Wu, Kailang; Liu, Xiaohong; Rao, Lang; Liu, Fang; Liu, Yingle; Wu, Jianguo

doi:10.1038/s41467-017-02645-3

Cited by 179 publications

(194 citation statements)

References 54 publications

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“…The role of CUL1 in regulation of the NLRP3 inflammasome was determined in a reconstructed NLRP3 inflammasome system, in which HEK293T cells were cotransfected with plasmids encoding NLRP3 inflammasome components (NLRP3, ASC, and pro–Casp‐1) and the substrate pro‐IL‐1β (25, 26). IL‐1β secretion, IL‐1β (p17) cleavage, and Casp–1 (p20) maturation were detected ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation

et al. 2019

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Activation of the NACHT, leucine‐rich repeat, and pyrin domains‐containing protein 3 (collectively known as NLRP3) inflammasome plays a key role in host immune response, which is the first line of defense against cellular stresses and pathogen infections. However, excessive inflammasome activation damages host cells, and therefore it must be precisely controlled. Here, we discover that Cullin1 (CUL1), a key component of the Skp1‐Cullin1‐F‐box E3 ligase, plays a critical role in controlling the NLRP3 inflammasome. CUL1 represses inflammasome assembly in cultured cells, suppresses NLRP3 function in human monocytic cell line macrophages, and attenuates inflammatory responses in mouse model. Detailed studies demonstrate that CUL1 interacts with NLRP3 and promotes NLRP3 ubiquitination, but not protein degradation, to repress the NLRP3 inflammasome activation. Moreover, upon inflammatory stimuli, including ATP and nigericin treatments, CUL1 disassociates from NLRP3 to release the repression of the NLRP3 inflammasome. Thus, this study reveals a distinct and unique mechanism underlying the control of systematic activation of the NLRP3 inflammasome.—Wan, P., Zhang, Q., Liu, W., Jia, Y., Ai, S., Wang, T., Wang, W., Pan, P., Yang, G., Xiang, Q., Huang, S., Yang, Q., Zhang, W., Liu, F., Tan, Q., Zhang, W., Wu, K., Liu, Y., Wu, J. Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation. FASEB J. 33, 5793–5807 (2019). http://www.fasebj.org

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Section: Resultsmentioning

confidence: 99%

“…As previously described (25), the cell lysates were mixed with SDS‐loading buffer for Western blot analyses using indicating antibodies. The pellets were washed with PBS 3 times and were cross‐linked using fresh DSS (2 mM; MilliporeSigma) at 37°C for 30 min.…”

Section: Methodsmentioning

confidence: 99%

Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation

et al. 2019

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“…Picornavirus has come up with a more dramatic strategy to trigger MDA5 and RIG‐I cleavage and degradation by using host caspases (Barral et al , ). Accumulating evidence from other groups revealed that inflammasome activation is necessary during ZIKV infection (Khaiboullina et al , ; Wang et al , ). Our in vivo experiments also suggest that NLRP3 inflammasome deficiency protects mice from ZIKV infection.…”

Section: Discussionmentioning

confidence: 99%

Zika virus elicits inflammation to evade antiviral response by cleaving cGAS via NS 1‐caspase‐1 axis

et al. 2018

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Viral infection triggers host innate immune responses, which primarily include the activation of type I interferon (IFN) signaling and inflammasomes. Here, we report that Zika virus (ZIKV) infection triggers NLRP3 inflammasome activation, which is further enhanced by viral non-structural protein NS1 to benefit its replication. NS1 recruits the host deubiquitinase USP8 to cleave K11-linked poly-ubiquitin chains from caspase-1 at Lys134, thus inhibiting the proteasomal degradation of caspase-1. The enhanced stabilization of caspase-1 by NS1 promotes the cleavage of cGAS, which recognizes mitochondrial DNA release and initiates type I IFN signaling during ZIKV infection. NLRP3 deficiency increases type I IFN production and strengthens host resistance to ZIKV and Taken together, our work unravels a novel antagonistic mechanism employed by ZIKV to suppress host immune response by manipulating the interplay between inflammasome and type I IFN signaling, which might guide the rational design of therapeutics in the future.

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“…39,40 In this system, HEK293T cells were co-transfected with plasmids encoding the NLRP3 inflammasome components (NLRP3, ASC, and pro-Casp1) and the substrate (pro-IL-1β). 39,40 In this system, HEK293T cells were co-transfected with plasmids encoding the NLRP3 inflammasome components (NLRP3, ASC, and pro-Casp1) and the substrate (pro-IL-1β).…”

Section: Sumo1 Sumoylates Nlrp3 To Promote the Inflammasome Activationmentioning

confidence: 99%

SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation

et al. 2019

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contributed equally to this work.Abbreviations: AIM2, absent in melanoma 2; ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; BMDM, bone marrow-derived macrophage; Casp-1, caspase-1; FITC, fluorescein isothiocyanate; GAPDH, glyceraldehyde 3-phosphate; HEK293T, human embryonic kidney cell line; IL-1β, interleukin-1β; LDH, lactate dehydrogenase; LRR, leucine-rich repeat; NACHT, NAIP (neuronal apoptosis inhibitory protein), CIITA (MHC class II transcription activator), HET-E (incompatibility locus protein from Podospora anserina) and TP1 (telomerase-associated protein); NLRP3, NACHT, LRR, and PYD domains-containing protein 3; PYD, pyrin domain; SENP, SUMO-specific protease; shRNA, short hairpin RNA; SUMO, small ubiquitin-like modifier; TCA, trichloroacetic acid solution; THP-1, human monocytic cell line; TPA, phorbol-12-myristate-13-acetate; UBC9, ubiquitin-like conjugating enzyme 9. AbstractThe NLRP3 inflammasome regulates innate immune and inflammatory responses by promoting caspase1-dependent induction of pro-inflammatory cytokines. However, aberrant inflammasome activation causes diverse diseases, and thus inflammasome activity must be tightly controlled. Here, we reveal a molecular mechanism underlying the regulation of NLRP3 inflammasome. NLRP3 interacts with SUMO-conjugating enzyme (UBC9), which subsequently promotes small ubiquitin-like modifier 1 (SUMO1) to catalyze NLRP3 SUMOylation at residue Lys 204 . SUMO1-catalyzed SUMOylation of NLRP3 facilitates ASC oligomerization, inflammasome activation, and interleukin-1β secretion. Moreover, this study also reveals that SUMO-specific protease 3 (SENP3) is required for the deSUMOylation of NLRP3. Interestingly, SENP3 deSUMOylates NLRP3 to attenuate ASC recruitment and speck formation, the NLRP3 inflammasome activation, as well as IL-1β cleavage and secretion. In conclusion, we reveal that SUMO1-catalyzed SUMOylation and SENP3-mediated deSUMOylation of NLRP3 orchestrate the inflammasome activation. K E Y W O R D Sinflammasome, innate immune response, interleukin-1β, posttranslational modification, SUMO1catalyzed SUMOylation 1498 | SHAO et Al.

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Zika virus infection induces host inflammatory responses by facilitating NLRP3 inflammasome assembly and interleukin-1β secretion

Cited by 179 publications

References 54 publications

Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation

Cullin1 binds and promotes NLRP3 ubiquitination to repress systematic inflammasome activation

Zika virus elicits inflammation to evade antiviral response by cleaving cGAS via NS 1‐caspase‐1 axis

SUMO1 SUMOylates and SENP3 deSUMOylates NLRP3 to orchestrate the inflammasome activation

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