A Role for the Human Nucleotide-binding Domain, Leucine-rich Repeat-containing Family Member NLRC5 in Antiviral Responses

Marianna Hösel,Katja Lautz,Elisabeth Kremmer,Hildegard Büning,Maureen Menning,Thomas A. Kufer,Robert Schwarzenbacher,Paola Zigrino,Andreas Neerincx

doi:10.1074/jbc.m110.109736

Abstract

Proteins of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing family recently gained attention as important components of the innate immune system. Although over 20 of these proteins are present in humans, only a few members including the cytosolic pattern recognition receptors NOD1, NOD2, and NLRP3 have been analyzed extensively. These NLRs were shown to be pivotal for mounting innate immune response toward microbial invasion. Here we report on the characterization of human NLRC5 and provide evidence that this NLR has a function in innate immune responses. We found that NLRC5 is a cytosolic protein expressed predominantly in hematopoetic cells. NLRC5 mRNA and protein expression was inducible by the double-stranded RNA analog poly(I.C) and Sendai virus. Overexpression of NLRC5 failed to trigger inflammatory responses such as the NF-kappaB or interferon pathways in HEK293T cells. However, knockdown of endogenous NLRC5 reduced Sendai virus- and poly(I.C)-mediated type I interferon pathway-dependent responses in THP-1 cells and human primary dermal fibroblasts. Taken together, this defines a function for NLRC5 in anti-viral innate immune responses.

Highlights

Proteins of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing family recently gained attention as important components of the innate immune system
NLRC5 is an interesting exception in the NLR family. It has a typical NLR architecture but contains an effector domain, predicted to adopt a death domain (DD) fold without obvious homology to the caspase activation and recruitment domain (CARD) and pyrin domain (PYD) domains found in other NLRs
NLRC5 Structure and Expression—Sequence comparisons of NLRC5 show the same overall multidomain architecture composed of effector, NACHT, winged helix, superhelical, and leucine-rich repeat region (LRR) domains, found in all other human NLRs

Summary

Introduction

Proteins of the nucleotide-binding domain, leucine-rich repeat (NLR)-containing family recently gained attention as important components of the innate immune system. Poly(I1⁄7C) did not significantly induce NLRC5 mRNA (data not shown) or protein levels in THP-1 cells (Fig. 3C).

Results

Conclusion