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Transcriptional analysis of the three Nlrp1 paralogs in mice
Inka Sastalla1, Devorah Crown, Seth L Masters
1Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 33 North Drive, Bethesda, MD 20892-3202, USA. sastallai@niaid.nih.gov
Background:
Signals of danger and damage in the cytosol of cells are sensed by NOD-like receptors (NLRs), which are components of multiprotein complexes called inflammasomes. Inflammasomes activate caspase-1, resulting in IL-1-beta and IL-18 secretion and an inflammatory response. To date, the only known activator of rodent Nlrp1 is anthrax lethal toxin (LT), a protease secreted by the bacterial pathogen Bacillus anthracis. Although susceptibility of mouse macrophages to LT has been genetically linked to Nlrp1b, mice harbor two additional Nlrp1 paralogs in their genomes (Nlrp1a and Nlrp1c). However, little is known about their expression profile and sequence in different mouse strains. Furthermore, simultaneous expression of these paralogs may lead to competitional binding of Nlrp1b interaction partners needed for inflammasome activation, thus influencing macrophages susceptibility to LT. To more completely understand the role(s) of Nlrp1 paralogs in mice, we surveyed for their expression in a large set of LT-resistant and sensitive mouse macrophages. In addition, we provide sequence comparisons for Nlrp1a and report on previously unrecognized splice variants of Nlrp1b.
Results:
Our results show that macrophages from some inbred mouse strains simultaneously express different splice variants of Nlrp1b. In contrast to the highly polymorphic Nlrp1b splice variants, sequencing of expressed Nlrp1a showed the protein to be highly conserved across all mouse strains. We found that Nlrp1a was expressed only in toxin-resistant macrophages, with the sole exception of expression in LT-sensitive CAST/EiJ macrophages.
Conclusions:
Our data present a complex picture of Nlrp1 protein variations and provide a basis for elucidating their roles in murine macrophage function. Furthermore, the high conservation of Nlrp1a implies that it might be an important inflammasome sensor in mice.
Insights
NOD-like receptors (NLRs) sense cellular danger. Researchers investigated Nlrp1 paralogs in mice, finding variations in Nlrp1b splice variants and conserved Nlrp1a, suggesting roles in inflammasome sensing and macrophage responses.
Area of Science:
- Immunology
- Cellular Biology
- Genetics
Background:
- NOD-like receptors (NLRs) are key sensors of cellular danger signals within the cytosol.
- NLRs form inflammasomes that activate caspase-1, driving inflammatory cytokine secretion (IL-1β, IL-18).
- Anthrax lethal toxin (LT) is the sole known activator of rodent Nlrp1, with susceptibility linked to Nlrp1b in mouse macrophages.
Purpose of the Study:
- To investigate the expression profiles and sequences of Nlrp1 paralogs (Nlrp1a, Nlrp1b, Nlrp1c) in LT-resistant and LT-sensitive mouse macrophages.
- To understand how Nlrp1 paralog variations might influence macrophage susceptibility to LT.
- To identify potential roles of Nlrp1 paralogs in inflammasome activation and immune responses.
Main Methods:
- Surveyed Nlrp1 paralog expression across a diverse set of LT-resistant and LT-sensitive mouse macrophages.
- Performed sequence comparisons for Nlrp1a across different mouse strains.
- Identified and characterized splice variants of Nlrp1b.
Main Results:
- Macrophages from various inbred mouse strains exhibited co-expression of different Nlrp1b splice variants.
- Nlrp1a protein sequences were highly conserved across all tested mouse strains.
- Nlrp1a expression was predominantly observed in LT-resistant macrophages, with a notable exception in LT-sensitive CAST/EiJ macrophages.
Conclusions:
- Mouse Nlrp1 paralogs display significant variation, particularly in Nlrp1b splice variants, complicating their functional roles.
- The high conservation of Nlrp1a suggests it may function as a critical inflammasome sensor in mice.
- These findings provide a foundation for further research into the specific functions of Nlrp1 paralogs in murine macrophage biology and inflammasome regulation.
