Troy binding to lymphotoxin-alpha activates NF kappa B mediated transcription.
Troy is a TNFR superfamily member that is highly expressed in developing hair follicles. Its possible function and ligand in skin have, however, been unknown. Here we demonstrate that an immunomodulatory cytokine, lymphotoxin-alpha (LTalpha), is a functional ligand of Troy by 3 biochemical approaches: (1) Immunoprecipitation assays revealed that LTalpha, but not LTbeta or any obligate combination of LTalpha and LTbeta, binds to Troy. (2) Co-transfection of LTalpha with Troy sharply upregulated NFkappaB reporter transcription, whereas LTbeta or a combination of LTalpha and LTbeta did not. (3) Recombinant LTalpha protein upregulated NFkappaB activity through Troy in a dosedependent manner. We further found that LTalpha is expressed in dermal papillae of developing hair follicles, whereas Troy was expressed in adjacent matrix region. This suggested involvement of LTalpha-Troy signaling in mesenchyme-epithelium interactions during hair follicle development. However, in Troy mutant mice that we generated, hair subtype composition and morphology were altered slightly if at all. The present study thus suggested a subtle function of the newly identified LTalpha-Troy pathway in skin appendage development, however, it may have an additional action compensated by a parallel EDA signaling pathway.
Hashimoto
Tsuyoshi
T
Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Schlessinger
David
D
Cui
Chang-Yi
CY
D000818:Animals; D002460:Cell Line; D005260:Female; D018859:Hair Follicle / Q000166:cytology / Q000254:growth & development; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D011485:Protein Binding / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*
D008233:Lymphotoxin-alpha; D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; C409471:Tnfrsf19 protein, mouse