NF-kappa B-inducing kinase regulates selected gene expression in the Nod2 signaling pathway.
The innate immune system surveys the extra- and intracellular environment for the presence of microbes. Among the intracellular sensors is a protein known as Nod2, a cytosolic protein containing a leucine-rich repeat domain. Nod2 is believed to play a role in determining host responses to invasive bacteria. A key element in upregulating host defense involves activation of the NF-kappaB pathway. It has been suggested through indirect studies that NF-kappaB-inducing kinase, or NIK, may be involved in Nod2 signaling. Here we have used macrophages derived from primary explants of bone marrow from wild-type mice and mice that either bear a mutation in NIK, rendering it inactive, or are derived from NIK-/- mice, in which the NIK gene has been deleted. We show that NIK binds to Nod2 and mediates induction of specific changes induced by the specific Nod2 activator, muramyl dipeptide, and that the role of NIK occurs in settings where both the Nod2 and TLR4 pathways are activated by their respective agonists. Specifically, we have linked NIK to the induction of the B-cell chemoattractant known as BLC and suggest that this chemokine may play a role in processes initiated by Nod2 activation that lead to improved host defense.
Department of Immunology, IMM-12, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
Qilin
Q
Pan
Vladimir
V
Kravchenko
Alex
A
Katz
Shuang
S
Huang
Masayuki
M
Ii
John C
JC
Mathison
Koichi
K
Kobayashi
Richard A
RA
Flavell
Robert D
RD
Schreiber
David
D
Goeddel
Richard J
RJ
Ulevitch
D000818:Animals; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002460:Cell Line; D002478:Cells, Cultured; D054382:Chemokine CXCL13; D019743:Chemokines, CXC / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D053473:Nod2 Signaling Adaptor Protein; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D000097782:NF-kappaB-Inducing Kinase
D018797:Cell Cycle Proteins; D054382:Chemokine CXCL13; D019743:Chemokines, CXC; D047908:Intracellular Signaling Peptides and Proteins; D053473:Nod2 Signaling Adaptor Protein; D017346:Protein Serine-Threonine Kinases; D000097782:NF-kappaB-Inducing Kinase; C486386:Cxcl13 protein, mouse; C495945:Nod2 protein, mouse; C111664:protein p52, mammalian