NOD2-C2 - a novel NOD2 isoform activating NF-κB in a muramyl dipeptide-independent manner

Marcel Kramer,Janne Boeck,Philip Rosenstiel,Klaus Huse,Stefan Schreiber,Matthias Platzer,Daniela Reichenbach,Christoph Kaether

doi:10.1186/1756-0500-3-224

Abstract

BackgroundThe innate immune system employs several receptor families that form the basis of sensing pathogen-associated molecular patterns. NOD (nucleotide-binding and oligomerization domain) like receptors (NLRs) comprise a group of cytosolic proteins that trigger protective responses upon recognition of intracellular danger signals. NOD2 displays a tandem caspase recruitment domain (CARD) architecture, which is unique within the NLR family.FindingsHere, we report a novel alternative transcript of the NOD2 gene, which codes for a truncated tandem CARD only protein, called NOD2-C2. The transcript isoform is highest expressed in leucocytes, a natural barrier against pathogen invasion, and is strictly linked to promoter usage as well as predominantly to one allele of the single nucleotide polymorphism rs2067085. Contrary to a previously identified truncated single CARD NOD2 isoform, NOD2-S, NOD2-C2 is able to activate NF-κB in a dose dependent manner independently of muramyl dipeptide (MDP). On the other hand NOD2-C2 competes with MDPs ability to activate the NOD2-driven NF-κB signaling cascade.ConclusionNOD2 transcripts having included an alternative exon downstream of exon 3 (exon 3a) are the endogenous equivalents of a previously described in vitro construct with the putative protein composed of only the two N-terminal CARDs. This protein form (NOD2-C2) activates NF-κB independent of an MDP stimulus and is a potential regulator of NOD2 signaling.

Highlights

The innate immune system employs several receptor families that form the basis of sensing pathogen-associated molecular patterns
The NLRs family consists of more than 20 related members defined by a tripartite structure consisting of: (i) a variable N-terminal proteinprotein interaction domain, defined by the caspase recruitment domain (CARD), pyrin domain (PYD), or the baculovirus inhibitor domain (BIR); (ii) a centrally located NOD domain facilitating self-oligomerization
We present an endogenous NOD2 alternative transcript coding for a protein containing the two CARDs only, NOD2-C2

Summary

Introduction

The innate immune system employs several receptor families that form the basis of sensing pathogen-associated molecular patterns. The innate immune system uses several molecules that sense pathogen-associated molecular patterns (PAMPs) including Toll-like, RIG-1 (retinoic acid inducible gene protein 1)-like and the NOD (nucleotide-binding and oligomerization domain)-like receptors (NLRs) to trigger a protective response against intracellular danger signals, e.g. cytoinvasive pathogens. The NLRs family consists of more than 20 related members defined by a tripartite structure consisting of: (i) a variable N-terminal proteinprotein interaction domain, defined by the caspase recruitment domain (CARD), pyrin domain (PYD), or the baculovirus inhibitor domain (BIR); (ii) a centrally located NOD domain facilitating self-oligomerization recognition, NOD1/2 undergo conformational changes and self-oligomerization This process is followed by recruitment and activation of the serine threonine kinase RIP2 (receptor interacting protein 2) via homophilic CARD/CARD interaction, which is essential for the activation of NF-B and MAPKs [7,8,9]. A recent genome-wide association study of Leprosy identified NOD2 sequence variants to be significantly associated with affected status [19]

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