CARD6 is interferon inducible but not involved in nucleotide-binding oligomerization domain protein signaling leading to NF-kappaB activation.
We have previously reported the cloning and characterization of CARD6, a caspase recruitment domain (CARD)-containing protein that is structurally related to the interferon (IFN)-inducible GTPases. CARD6 associates with microtubules and with receptor-interacting protein 2 (RIP2). RIP2 mediates NF-kappaB activation induced by the intracellular nucleotide-binding oligomerization domain (NOD) receptors that sense bacterial peptidoglycan. Here we report that the expression of CARD6 and RIP2 in bone marrow-derived macrophages is rapidly induced by beta IFN and gamma IFN. This IFN-induced upregulation of CARD6 is suppressed by lipopolysaccharide (LPS), in contrast to LPS's enhancement of IFN-induced RIP2 upregulation. We generated CARD6-deficient (CARD6(-/-)) mice and carried out extensive analyses of signaling pathways mediating innate and adaptive immune responses, including the NOD pathways, but did not detect any abnormalities. Moreover, CARD6(-/-) mice were just as susceptible as wild-type mice to infection by Salmonella enterica serovar Typhimurium, Listeria monocytogenes, Candida albicans, lymphocytic choriomeningitis virus, or mouse adenovirus type 1. Thus, although structural and in vitro analyses strongly suggest an important role for CARD6 in immune defense, the physiological function of CARD6 remains obscure.
Dufner
Almut
A
Campbell Family Institute for Breast Cancer Research and Ontario Cancer Institute, Toronto, Ontario M5G 2C1, Canada. a_dufner@yahoo.com
Duncan
Gordon S
GS
Wakeham
Andrew
A
Elford
Alisha R
AR
Hall
Håkan T
HT
Ohashi
Pamela S
PS
Mak
Tak W
TW
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002999:Clone Cells; D003433:Crosses, Genetic; D018274:Electroporation; D004622:Embryo, Mammalian; D053595:Embryonic Stem Cells / Q000166:cytology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006579:Heterozygote; D007372:Interferons / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008845:Microinjections; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D053472:Nod Signaling Adaptor Proteins / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D015398:Signal Transduction / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D053468:CARD Signaling Adaptor Proteins; C527301:Card6 protein, mouse; D016328:NF-kappa B; D053472:Nod Signaling Adaptor Proteins; D011994:Recombinant Proteins; D007372:Interferons