Modulation of innate immunity by nucleotide binding: biochemical and functional characterization of a CATERPILLER/NLR protein, Monarch-1/NLRP12 Public Deposited

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  • March 21, 2019
Creator
  • Ye, Zhengmao
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • The recently discovered Nucleotide Binding Domain-Leucine Rich Repeat (NLR) gene family is conserved from plants to mammals and several members are associated with human autoinflammatory or immunodeficiency disorders. This family is defined by a central nucleotide binding domain that contains the highly conserved Walker A and Walker B motifs. Although the nucleotide binding domain is a defining feature of this family, it has not been extensively studied in its purified form. In this thesis, we show that purified Monarch-1/NLRP12, an NLR protein that negatively regulates NF-[kappa]B signaling, specifically binds ATP and exhibits ATP hydrolysis activity. Intact Walker A/B motifs are required for this activity. These motifs are also required for Monarch-1 to undergo self-oligomerization, TLR- or CD40L- activated association with NIK and IRAK-1, degradation of NIK, and inhibition of IRAK-1 phosphorylation. Stable expression of a Walker A/B mutant in THP-1 monocytes results in increased production of proinflammatory cytokines and chemokines to an extent comparable to cells in which Monarch-1 is silenced via shRNA. In addition, the functional role of conserved motifs in Monarch-1 NBD domain is examined. The results of this study are consistent with a model wherein ATP binding regulates the anti-inflammatory activity of Monarch-1.
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  • In Copyright
Advisor
  • Ting, Jenny P.-Y.
Degree granting institution
  • University of North Carolina at Chapel Hill
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