Characterization of an NLRP1 Inflammasome from Zebrafish Reveals a Unique Sequential Activation Mechanism Underlying Inflammatory Caspases in Ancient Vertebrates

Li, Jiangyuan; Gao, Ke; Shao, Tong; Fan, Dongdong; Hu, Chong-bin; Sun, Cen-Cen; Dong, Wei-Ren; Lin, Aifu; Xiang, Lei; Shao, Jian-zhong

doi:10.4049/jimmunol.1800498

Cited by 59 publications

(56 citation statements)

References 71 publications

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“…For antibacterial assay, the Dr cGASa/b/ Dr STING morphornts and wild‐type control embryos at 24 hours post fertilization (hpf) were exposed to A hydrophila or Edwardsiella tarda ( E tarda , 1 × 10 8 CFU/mL) 34,39 . After immersion in the bacterial suspension for 5 hours, the mortality of each group was recorded at 12‐72 hours post infection (hpi).…”

Section: Methodsmentioning

confidence: 99%

Characterization of cGAS homologs in innate and adaptive mucosal immunities in zebrafish gives evolutionary insights into cGAS‐STING pathway

Liu

Xiao-feng

et al. 2020

FASEB j.

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Cyclic GMP‐AMP synthase (cGAS) is one of the most‐characterized cytoplasmic DNA sensors in humans and other mammals. However, knowledge about cGAS homologs in nonmammalian species remains limited. In this study, we report the molecular and functional identification of two cGAS homologs, namely, DrcGASa and DrcGASb, from a zebrafish (Danio rerio) model. DrcGASa and DrcGASb share the same overall conservative structural architectures and functional domains/residues to mammalian cGASs. Both homologs synthesized a 2′3′‐cGAMP isomer but not a 3′3′‐cGAMP isomer via oligomerization in response to DNA stimulation. Overexpression of DrcGASa/b in HEK293T cells and zebrafish embryos significantly activated NF‐κB and IFN‐I signaling pathways in a STING‐dependent manner. Knockdown of DrcGASa or DrSTING impaired such activations, thereby reducing the host innate immunity against bacterial and viral infections. DrcGASa, but not DrcGASb, was involved in immunoglobulin Z‐mediated mucosal immunity in gill‐associated lymphoid tissue, suggesting differential functions between the two DrcGASs. This reaction was associated with the DrcGAS‐DrSTING‐IFNφ1 signaling axis in GALT’s γδ T cells. Our findings provide experimental evidence that a modern cGAS‐STING pathway that mainly participates in IFN‐mediated immunity originated from teleost fish based on the functional constraint of cGAS and STING proteins during vertebrate evolution.

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Section: Methodsmentioning

confidence: 99%

Characterization of cGAS homologs in innate and adaptive mucosal immunities in zebrafish gives evolutionary insights into cGAS‐STING pathway

Liu

Xiao-feng

et al. 2020

FASEB j.

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“…Once formed, the oligomerized CARDs are sufficient to activate downstream inflammasome signaling. This model is also likely to be valid for NLRP1/CARD8 homologues from other species, as the arrangement of the FIIND and CARD domains are conserved across evolution 22,23 .…”

Section: Nlrp1-card Oligomerization and Dramatically Lowers Its Thresmentioning

confidence: 96%

Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

Gong

Robinson²,

et al. 2020

Preprint

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Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related NLR proteins, NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, the molecular mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIIND UPA -CARD) of NLRP1 and CARD8 self-oligomerize to trigger the assembly of distinct inflammasome complexes. Recombinant FIIND UPA -CARD of NLRP1 forms a two-layered filament, with an inner core composed of oligomerized CARD domains and the outer layer consisting of FIIND UPA rings.Biochemically, oligomerized NLRP1-CARD is sufficient to drive ASC speck formation in cultured human cells via filament formation-a process that is greatly enhanced by NLRP1-FIIND UPA , which forms ring-like oligomers in vitro. In addition, we report the cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments at 3.7 Å, which uncovers unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide unique structural insight into the mechanisms of activation for human NLRP1 and CARD8, uncovering an unexpected level of specificity in inflammasome signaling mediated by heterotypic CARD domain interactions.

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“…This holds true for Gobiidae NLR-C groups, since only group 5 NLRs can carry an N-terminal PYD domain and/or a C-terminal B30.2 domain [102], similar to the zebrafish (Danio rerio) group 1 and 2 NLRs (Table 4). In contrast, some group 6 NLRs have C-terminal CARD domains, which in both human (Homo sapiens) and zebrafish (Danio rerio) are attached to specific inflammasome-associated NLR-B genes [107]. The round goby C-terminal CARD-containing NLRs are found on the same few scaffolds and share a high degree of sequence similarity, indicative of a recent expansion.…”

Section: Response To the Environment: Immune Systemmentioning

confidence: 99%

“…The fish inflammasome complex is somewhat poorly characterized, and maturation of IL-1 by inflammasomeactivated Caspase 1 cleavage is a matter of debate because teleost IL-1 proteins lack the conserved caspase cleavage site present in mammalian IL-1b and IL-18 [133]. However, zebrafish (Danio rerio) Caspase 1 can utilize an alternative site to cleave and mature IL-1 [107,134], and the presence of components such as ASC, caspases, and pro-IL1 and pro-IL18 further supports a role for inflammasomes in fish, particularly since zebrafish (Danio rerio) ASC oligomerize and form "specks" as seen in mammals [107]. The round goby with its strong inflammasome system may therefore present an attractive system to explore the molecular dynamics of inflammasome activation in fish.…”

Section: Response To the Environmentmentioning

confidence: 99%

The round goby genome provides insights into mechanisms that may facilitate biological invasions

et al. 2020

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Background: The invasive benthic round goby (Neogobius melanostomus) is the most successful temperate invasive fish and has spread in aquatic ecosystems on both sides of the Atlantic. Invasive species constitute powerful in situ experimental systems to study fast adaptation and directional selection on short ecological timescales and present promising case studies to understand factors involved the impressive ability of some species to colonize novel environments. We seize the unique opportunity presented by the round goby invasion to study genomic substrates potentially involved in colonization success. Results: We report a highly contiguous long-read-based genome and analyze gene families that we hypothesize to relate to the ability of these fish to deal with novel environments. The analyses provide novel insights from the large evolutionary scale to the small species-specific scale. We describe expansions in specific cytochrome P450 enzymes, a remarkably diverse innate immune system, an ancient duplication in red light vision accompanied by red skin fluorescence, evolutionary patterns of epigenetic regulators, and the presence of osmoregulatory genes that may have contributed to the round goby's capacity to invade cold and salty waters. A recurring theme across all analyzed gene families is gene expansions. Conclusions: The expanded innate immune system of round goby may potentially contribute to its ability to colonize novel areas. Since other gene families also feature copy number expansions in the round goby, and since other Gobiidae also feature fascinating environmental adaptations and are excellent colonizers, further long-read genome approaches across the goby family may reveal whether gene copy number expansions are more generally related to the ability to conquer new habitats in Gobiidae or in fish.

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Characterization of an NLRP1 Inflammasome from Zebrafish Reveals a Unique Sequential Activation Mechanism Underlying Inflammatory Caspases in Ancient Vertebrates

Cited by 59 publications

References 71 publications

Characterization of cGAS homologs in innate and adaptive mucosal immunities in zebrafish gives evolutionary insights into cGAS‐STING pathway

Characterization of cGAS homologs in innate and adaptive mucosal immunities in zebrafish gives evolutionary insights into cGAS‐STING pathway

Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8

The round goby genome provides insights into mechanisms that may facilitate biological invasions

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