NLRP11

This gene encodes a protein with an N-terminal pyrin death (PYD) domain and nucleoside triphosphate hydrolase (NACHT) domain, and a C-terminal leucine-rich repeats (LRR) region. It contains a total of 14 LRRs and 1033 amino acids.[3][4]

NLRP11 is a primate-specific gene and is not found in mice A study on the evolution of mammalian reproduction-related NLRPs found that NLRP11 is part of a family cluster of genes that duplicated before the divergence of mammals.[7]

Bacterial lipopolysaccharide (LPS) is an endotoxin that can lead to lethal infection sepsis by activating innate immune responses. Cytoplasmic LPS(cLPS) induces the assembly of an inflammasome that contains caspases-4/5 in humans or caspase-11 in mice NLRP11 serves as a pattern recognition receptor for cLPS and can result in caspase-4 inflammasome activation.[8]

There is also a novel role of NLRP11 in the regulation of inflammatory responses in human cells. In primates, NLRP11 also serves as a conserved negative regulator of TLR signaling. NLRP11 acts as a negative regulator of type I IFN and virus-induced apoptosis by disrupting the Mitochondrial antiviral-signaling protein (MAVS) signalosome activity. ATP-dependent RNA helicase DDX3X is a novel binding partner of NLRP11. NLRP11 suppressed the positive effect of DDX3X on NLRP3 inflammasome-mediated caspase-1 activation. Research also suggested that there might be a role of NLRP11 function in innate immunity. NLRP11 and DDX3X might become promising targets for the modulation of innate immune responses.[9]

Upon viral infection, Type I IFN activates NLRP11, and upon activation, it translocates to mitochondria to interact with MAVS. NLRP11 degrades TRAF6 using MAVS to attenuate the production of type I IFNs and virus-induced apoptosis. NLRP11 acts as a negative regulator of type I IFN and virus-induced apoptosis via disrupting the activity of MAVS signalosome.[10]

In human macrophages, NLRP11 is an indispensable component of the NLRP3 inflammasome. The most studied inflammasome sensor molecule of the NLR family is NLRP3, and it contains an amino-terminal PYRIN (PYD) domain, a nucleotide-binding NACHT domain, and a carboxyterminal leucine-rich repeat (LRR) domain. The ATP binding is required for NLRP3 activation, NACHT domain of NLRP3 contains ATPase activity, and mutation of this site reduces ATP binding, caspase-1 activation, IL-1 production, cell death, macromolecular complex formation, and its association with apoptosis-associated speck-like protein containing a CARD (ASC).

There is an interaction between NLRP11, NLRP3, and ASC. NLRP3 inflammasome activation is inhibited by specific deletion of NLRP11, which leads to inhibition of ASC polymerization, caspase-1 activation, and subsequent cytokine release. NLRP3 mutations that cause cryopyrin-associated periodic syndrome (CAPS) also require NLRP11 for inflammasome responses. The complex biology of inflammasome regulation is being explored, and the role of NLRP11 in diseases is partially understood.[11]