Ndfip1 protein promotes the function of itch ubiquitin ligase to prevent T cell activation and T helper 2 cell-mediated inflammation.
Nedd4 family interacting protein-1 (Ndfip1) is a protein whose only known function is that it binds Nedd4, a HECT-type E3 ubiquitin ligase. Here we show that mice lacking Ndfip1 developed severe inflammation of the skin and lung and died prematurely. This condition was due to a defect in Ndfip1(-/-) T cells. Ndfip1(-/-) T cells were activated, and they proliferated and adopted a T helper 2 (Th2) phenotype more readily than did their Ndfip1(+/+) counterparts. This phenotype resembled that of Itchy mutant mice, suggesting that Ndfip1 might affect the function of Itch, an E3 ubiquitin ligase. We show that T cell activation promoted both Ndfip1 expression and its association with Itch. In the absence of Ndfip1, JunB half-life was prolonged after T cell activation. Thus, in the absence of Ndfip1, Itch is inactive and JunB accumulates. As a result, T cells produce Th2 cytokines and promote Th2-mediated inflammatory disease.
Oliver
Paula M
PM
Howard Hughes Medical Institute, National Jewish Medical and Research Center and University of Colorado Health Sciences Center, Denver, Colorado 80206, USA.
Cao
Xiao
X
Worthen
George Scott
GS
Shi
Peijun
P
Briones
Natalie
N
MacLeod
Megan
M
White
Janice
J
Kirby
Patricia
P
Kappler
John
J
Marrack
Philippa
P
Yang
Baoli
B
D000818:Animals; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000096:biosynthesis; D005434:Flow Cytometry; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D016755:Proto-Oncogene Proteins c-jun / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000276:immunology / Q000378:metabolism*
D002352:Carrier Proteins; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C499188:Ndfip1 protein, mouse; D016755:Proto-Oncogene Proteins c-jun; C471637:Itch protein, mouse; D044767:Ubiquitin-Protein Ligases