NOD2 and reproduction-associated NOD-like receptors have been lost during the evolution of pangolins

Margarita Salova,Leopold Eckhart,Erwin Tschachler,Wolfgang Sipos

doi:10.1007/s00251-021-01230-9

Margarita Salova, Leopold Eckhart + Show 2 more

Open Access

https://doi.org/10.1007/s00251-021-01230-9

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Abstract

NOD-like receptors (NLRs) are sensors of pathogen-associated molecular patterns with critical roles in the control of immune responses and programmed cell death. Recent studies have revealed inter-species differences in mammalian innate immune genes and a particular degeneration of nucleic acid sensing pathways in pangolins, which are currently investigated as potential hosts for zoonotic pathogens. Here, we used comparative genomics to determine which NLR genes are conserved or lost in pangolins and related mammals. We show that NOD2, which is implicated in sensing bacterial muramyl dipeptide and viral RNA, is a pseudogene in pangolins, but not in any other mammalian species investigated. NLRC4 and NAIP are absent in pangolins and canine carnivorans, suggesting convergent loss of cytoplasmic sensing of bacterial flagellin in these taxa. Among NLR family pyrin domain containing proteins (NLRPs), skin barrier-related NLRP10 has been lost in pangolins after the evolutionary divergence from Carnivora. Strikingly, pangolins lack all NLRPs associated with reproduction (germ cells and embryonic development) in other mammals, i.e., NLRP2, 4, 5, 7, 8, 9, 11, 13, and 14. Taken together, our study shows a massive degeneration of NLR genes in pangolins and suggests that these endangered mammals may have unique adaptations of innate immunity and reproductive cell biology.

Highlights

Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a family of proteins involved in the defense against pathogens and in reproduction (Fig. 1)
The primordial function of NOD-like receptors (NLRs) is the detection of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which include bacterial cell wall components, such as fragments of peptidoglycan that are sensed by NOD1 and NOD2 (Philpott et al 2014; Wolf and Underhill 2018), viral RNAs which are sensed by NOD2 and NLRP6 (Sabbah et al 2009; Wang 2015; Liu and Gack 2020), and others (Kuss-Duerkop et al 2020; Pei et al 2021)
Comparative analysis of NOD2, which had been reported to be involved in sensing single-stranded RNA (Sabbah et al 2009), showed that a NOD2 gene locus is present in pangolins, dog, cattle, and human (Fig. 2a)

Summary

Introduction

Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a family of proteins involved in the defense against pathogens and in reproduction (Fig. 1). The NOD/NACHT domain mediates self-oligomerization upon binding of a ligand to LRRs. In addition, NLRs contain other domains such as 1 or 2 caspase recruitment domains (CARDs) or a pyrin domain (PYD), which mediate interactions with other proteins to control the initiation of inflammation, programmed cell death and other processes (Inohara et al 2005; Fritz et al 2006; Ting et al.2008; Zhang et al 2010; Elinav et al 2011; Zhong et al 2013; Geddes et al 2009; Heim et al 2019; Kienes et al 2021; Danis et al 2021). NLRs were originally identified as activators of inflammation and immune responses, but later research has demonstrated anti-inflammatory roles of

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