The CATERPILLER protein monarch-1 is an antagonist of toll-like receptor-, tumor necrosis factor alpha-, and Mycobacterium tuberculosis-induced pro-inflammatory signals.
The CATERPILLER (CLR, also NOD and NLR) proteins share structural similarities with the nucleotide binding domain (NBD)-leucine-rich repeat (LRR) superfamily of plant disease-resistance (R) proteins and are emerging as important immune regulators in animals. CLR proteins contain NBD-LRR motifs and are linked to a limited number of distinct N-terminal domains including transactivation, CARD (caspase activation and recruitment), and pyrin domains (PyD). The CLR gene, Monarch-1/Pypaf7, is expressed by resting primary myeloid/monocytic cells, and its expression in these cells is reduced by Toll-like receptor (TLR) agonists tumor necrosis factor (TNF) alpha and Mycobacterium tuberculosis. Monarch-1 reduces NFkappaB activation by TLR-signaling molecules MyD88, IRAK-1 (type I interleukin-1 receptor-associated protein kinase), and TRAF6 (TNF receptor (TNFR)-associated factor) as well as TNFR signaling molecules TRAF2 and RIP1 but not the downstream NFkappaB subunit p65. This indicates that Monarch-1 is a negative regulator of both TLR and TNFR pathways. Reducing Monarch-1 expression with small interference RNA in myeloid/monocytic cells caused a dramatic increase in NFkappaB activation and cytokine expression in response to TLR2/TLR4 agonists, TNFalpha, or M. tuberculosis infection, suggesting that Monarch-1 is a negative regulator of inflammation. Because Monarch-1 is the first CLR protein that interferes with both TLR2 and TLR4 activation, the mechanism of this interference is significant. We find that Monarch-1 associates with IRAK-1 but not MyD88, resulting in the blockage of IRAK-1 hyperphosphorylation. Mutants containing the NBD-LRR or PyD-NBD also blocked IRAK-1 activation. This is the first example of a CLR protein that antagonizes inflammatory responses initiated by TLR agonists via interference with IRAK-1 activation.
Williams
Kristi L
KL
Lineberger Comprehensive Cancer Center, Division of Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Lich
John D
JD
Duncan
Joseph A
JA
Reed
William
W
Rallabhandi
Prasad
P
Moore
Christopher
C
Kurtz
Sherry
S
Coffield
V McNeil
VM
Accavitti-Loper
Mary A
MA
Su
Lishan
L
Vogel
Stefanie N
SN
Braunstein
Miriam
M
Ting
Jenny P-Y
JP
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D020816:Amino Acid Motifs; D000943:Antigens, Differentiation / Q000378:metabolism; D020169:Caspases / Q000737:chemistry; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000737:chemistry; D004797:Enzyme-Linked Immunosorbent Assay; D017930:Genes, Reporter; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation; D053592:Interleukin-1 Receptor-Associated Kinases; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism / Q000502:physiology*; D008156:Luciferases / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D000071198:Pyrin; D012313:RNA / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D015533:Transcriptional Activation; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
C119724:AGFG1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D016207:Cytokines; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; C000604192:MEFV protein, human; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; C476731:NLRP12 protein, human; D028861:Nuclear Pore Complex Proteins; D000071198:Pyrin; C498143:RELA protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D011971:Receptors, Immunologic; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D008156:Luciferases; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; D020169:Caspases