Characterization of an NLRP1 Inflammasome from Zebrafish Reveals a Unique Sequential Activation Mechanism Underlying Inflammatory Caspases in Ancient Vertebrates
NLRP1 inflammasome is one of the best-characterized inflammasomes in humans and other mammals. However, the existence of this inflammasome in nonmammalian species remains poorly understood. In this study, we report the molecular and functional identification of an NLRP1 homolog, NLRP1 ( NLRP1) from...
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Published in | The Journal of immunology (1950) Vol. 201; no. 7; pp. 1946 - 1966 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
01.10.2018
|
Online Access | Get full text |
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Summary: | NLRP1 inflammasome is one of the best-characterized inflammasomes in humans and other mammals. However, the existence of this inflammasome in nonmammalian species remains poorly understood. In this study, we report the molecular and functional identification of an NLRP1 homolog,
NLRP1 (
NLRP1) from a zebrafish (
) model. This
NLRP1 possesses similar structural architecture to mammalian NLRP1s. It can trigger the formation of a classical inflammasome for the activation of zebrafish inflammatory caspases (
Caspase [
Caspase]-A and
Caspase-B) and maturation of
IL-1β in a
ASC (
ASC)-dependent manner. In this process,
NLRP1 promotes the aggregation of
ASC into a filament with
ASC
core and
ASC
cluster. The assembly of
NLRP1 inflammasome depends on the CARD-CARD homotypic interaction between
NLRP1 and
ASC
core, and PYD-PYD interaction between
Caspase-A/B and
ASC
cluster. The FIIND domain in
NLRP1 is necessary for inflammasome assembly. To understand the mechanism of how the two
Caspases are coordinated in
NLRP1 inflammasome, we propose a two-step sequential activation model. In this model, the recruitment and activation of
Caspase-A/B in the inflammasome is shown in an alternate manner, with a preference for
Caspase-A followed by a subsequent selection for
Caspase-B. By using morpholino oligonucleotide-based knockdown assays, the
NLRP1 inflammasome was verified to play important functional roles in antibacterial innate immunity in vivo. These observations demonstrate that the NLRP1 inflammasome originated as early as in teleost fish. This finding not only gives insights into the evolutionary history of inflammasomes but also provides a favorable animal model for the study of NLRP1 inflammasome-mediated immunology and diseases. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-1767 1550-6606 |
DOI: | 10.4049/jimmunol.1800498 |