NLRP4 gene

The NLRP4 gene (NLRP4 is the acronym for: NLR Family Pyrin Domain Containing 4) is a protein-coding gene located on chromosome 19q13.43. The protein encoded by this gene(NLRP4 protein) belongs to the nucleotide-binding and leucine-rich receptor (NLR) family and (like other NLRP proteins) contains an N-terminal pyrin effector domain (PYD), a centrally located nucleotide binding and oligomerization domain (NACHT) and C-terminal leucine-rich repeats (LRR). The signaling pathways used include cytosolic sensors for pathogen-associated DNA and the innate immune system. An important paralog of this gene is NLRP3.

The encoded protein has a proven role as a negative regulator of autophagy (Jounai N et al. 2011) and type I interferon signaling pathways as a result of protein interactions with its NACHT domain (Sun RM et al. 2022). The PYD domain is also important for the inhibition of NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells).

The NLRP4 protein may be involved in inflammation and the recognition of cytosolic pathogen-associated molecular patterns (PAMPs) that are not intercepted by membrane-bound receptors. It acts as a negative regulator of the type I interferon signaling pathway by serving as an adaptor to promote DTX4-mediated ubiquitination of activated TBK1 and its subsequent degradation. Furthermore, it suppresses NF-kappaB induction by the cytokines TNFA and IL1B, suggesting that it acts at a convergence point in these two cytokine signaling pathways.

Impairment of NLRP4 by RNA interference leads to upregulation of the autophagic processm under physiological conditions. This is also observed in invasive bacterial infections, leading to an enhancement of the autophagic bactericidal process of group A streptococci. NLRP4 recruits to the subplasma membrane phagosomes containing group A streptococci and transiently detaches from Beclin1, suggesting that NLRP4 senses bacterial infection and enables the initiation of Beclin1-mediated autophagic responses (Jounai N et al. 2011; Wirawan E et al. 2012).

1. Jounai N et al. (2011) NLRP4 negatively regulates autophagic processes through an association with beclin1. J Immunol 186:1646-1655.
2. Sun RM et al. (2022) NLRP4 negatively regulates type I interferon response and influences the outcome in anti-programmed cell death protein (PD)-1/PD-ligand 1 therapy. Cancer Sci 113:838-851.
3. Wirawan E et al. (2012) Beclin1: a role in membrane dynamics and beyond. Autophagy 8: 6-17.