The anaphase-promoting complex protein 5 (AnapC5) associates with A20 and inhibits IL-17-mediated signal transduction.
IL-17 is the founding member of a family of cytokines and receptors with unique structures and signaling properties. IL-17 is the signature cytokine of Th17 cells, a relatively new T cell population that promotes inflammation in settings of infection and autoimmunity. Despite advances in understanding Th17 cells, mechanisms of IL-17-mediated signal transduction are less well defined. IL-17 signaling requires contributions from two receptor subunits, IL-17RA and IL-17RC. Mutants of IL-17RC lacking the cytoplasmic domain are nonfunctional, indicating that IL-17RC provides essential but poorly understood signaling contributions to IL-17-mediated signaling. To better understand the role of IL-17RC in signaling, we performed a yeast 2-hybrid screen to identify novel proteins associated with the IL-17RC cytoplasmic tail. One of the most frequent candidates was the anaphase promoting complex protein 7 (APC7 or AnapC7), which interacted with both IL-17RC and IL-17RA. Knockdown of AnapC7 by siRNA silencing exerted no detectable impact on IL-17 signaling. However, AnapC5, which associates with AnapC7, was also able to bind IL-17RA and IL-17RC. Moreover, AnapC5 silencing enhanced IL-17-induced gene expression, suggesting an inhibitory activity. Strikingly, AnapC5 also associated with A20 (TNFAIP3), a recently-identified negative feedback regulator of IL-17 signal transduction. IL-17 signaling was not impacted by knockdown of Itch or TAXBP1, scaffolding proteins that mediate A20 inhibition in the TNFα and IL-1 signaling pathways. These data suggest a model in which AnapC5, rather than TAX1BP1 and Itch, is a novel adaptor and negative regulator of IL-17 signaling pathways.
Division of Rheumatology and Clinical Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
Allen W
AW
Ho
Abhishek V
AV
Garg
Leticia
L
Monin
Michelle R
MR
Simpson-Abelson
Lauren
L
Kinner
Sarah L
SL
Gaffen
D020816:Amino Acid Motifs; D000818:Animals; D064193:Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D064195:Apc7 Subunit, Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D011416:Complement Factor D / Q000378:metabolism; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000378:metabolism*; D020381:Interleukin-17 / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D011485:Protein Binding; D025941:Protein Interaction Mapping; D021122:Protein Subunits / Q000378:metabolism; D053722:Receptors, Interleukin-17 / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D064193:Apc5 Subunit, Anaphase-Promoting Complex-Cyclosome; D064195:Apc7 Subunit, Anaphase-Promoting Complex-Cyclosome; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D020381:Interleukin-17; D047908:Intracellular Signaling Peptides and Proteins; D021122:Protein Subunits; D053722:Receptors, Interleukin-17; C490030:Rrad protein, mouse; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D011416:Complement Factor D; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse; D018631:ras Proteins