Evolution of the NLR gene family in vertebrates: insights into the origin of inflammasomes.

Abstract

Nucleotide binding domain leucine rich repeat proteins (NLRs) are a family of intracellular pattern recognition receptors which play an important role in innate immune system; as well as the regulation of many other immunity-related components and signalling pathways, such as MHCs, NF-Κβ, pyroptosis, inflammasomes or MAPK (Chou et al., 2023; Hansen et al., 2011). Some NLR proteins can also participate in the regulation of hematopoietic stem progenitors cells (HSCPs) emergence, expansion, and migration (Ratajczak & Kucia, 2021; Tyrkalska et al., 2019). Some NLR proteins also regulate different processes in mammalian reproduction such as fertilization (NLRP14) and embryogenesis (NLRP5/7) (Chou et al., 2023; Tian et al., 2009). Gene members of the NLR family are present across all metazoan lineages (Ting et al., 2008). However, NLR repertoires (gene catalogues and their functions) of most non-model vertebrate species are poorly studied, hindering further studies of the evolution and diversification of this important gene family. Here, we present a comprehensive screening of NLR genes in representative species of all major lineages of vertebrates, with a special focus on jawless vertebrates. Our in-depth phylogenetic analysis demonstrates that large lineage-specific expansions took place in most lineages of vertebrates, with classic inflammasome-forming NLRP genes appearing only in mammals. Mammalian NLRP genes early diversified into two distinct groups with different immune- and reproductive-related functions, each expanding separately. Altogether, our analyses suggest that gene duplication and expansion of NLR genes is likely associated with the origin of novel functions within the family, such as hematopoiesis regulation in mammals.