The HECT-type E3 ubiquitin ligase AIP2 inhibits activation-induced T-cell death by catalyzing EGR2 ubiquitination.
E3 ubiquitin ligases, which target specific molecules for proteolytic destruction, have emerged as key regulators of immune functions. Several E3 ubiquitin ligases, including c-Cbl, Cbl-b, GRAIL, Itch, and Nedd4, have been shown to negatively regulate T-cell activation. Here, we report that the HECT-type E3 ligase AIP2 positively regulates T-cell activation. Ectopic expression of AIP2 in mouse primary T cells enhances their proliferation and interleukin-2 production by suppressing the apoptosis of T cells. AIP2 interacts with and promotes ubiquitin-mediated degradation of EGR2, a zinc finger transcription factor that has been found to regulate Fas ligand (FasL) expression during activation-induced T-cell death. Suppression of AIP2 expression by small RNA interference upregulates EGR2, inhibits EGR2 ubiquitination and FasL expression, and enhances the apoptosis of T cells. Therefore, AIP2 regulates activation-induced T-cell death by suppressing EGR2-mediated FasL expression via the ubiquitin pathway.
Chen
An
A
Departments of Otolaryngology-Head and Neck Surgery and Molecular Microbiology and Immunology, University of Missouri-Columbia School of Medicine, One Hospital Dr., Columbia, MO 65212, USA.
Gao
Beixue
B
Zhang
Jingping
J
McEwen
Tamara
T
Ye
Shui Q
SQ
Zhang
Donna
D
Fang
Deyu
D
D000818:Animals; D017209:Apoptosis; D055162:Biocatalysis; D002478:Cells, Cultured; D051767:Early Growth Response Protein 2 / Q000378:metabolism*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism*; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D051638:Ether-A-Go-Go Potassium Channels; D053222:Fas Ligand Protein; C092509:KCNH6 protein, human; D034741:RNA, Small Interfering; C465283:WWP2 protein, human; C487995:Wwp2 protein, mouse; D044767:Ubiquitin-Protein Ligases