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Molecular and Cellular Biology, October 2009, p. 5348-5356, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00407-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

The HECT-Type E3 Ubiquitin Ligase AIP2 Inhibits Activation-Induced T-Cell Death by Catalyzing EGR2 Ubiquitination{triangledown}

An Chen,1,4 Beixue Gao,1 Jingping Zhang,1 Tamara McEwen,2 Shui Q. Ye,2,3 Donna Zhang,5 and Deyu Fang1,2,{dagger}*

Department of Otolaryngology-Head and Neck Surgery,1 Department of Molecular Microbiology and Immunology,2 Department of Surgery, University of Missouri School of Medicine, One Hospital Dr., Columbia, Missouri 65212,3 Department of Clinical Biochemistry, Third Military Medical University, Chongqing, People's Republic of China,4 Department of Pharmacology and Toxicology, University of Arizona, 1703 East Mabel Street, Tucson, Arizona 857215

Received 29 March 2009/ Returned for modification 10 June 2009/ Accepted 25 July 2009

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.

* Corresponding author. Mailing address: 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. Phone: (573) 882-4585. Fax: (573) 882-4287. E-mail: FangD{at}missouri.edu

{triangledown} Published ahead of print on 3 August 2009.

{dagger} Present address: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611.

Molecular and Cellular Biology, October 2009, p. 5348-5356, Vol. 29, No. 19
0270-7306/09/$08.00+0     doi:10.1128/MCB.00407-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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