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Molecular and Cellular Biology, July 2001, p. 4626-4635, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4626-4635.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Downregulation of CIITA Function by Protein Kinase A (PKA)-Mediated Phosphorylation: Mechanism of Prostaglandin E, Cyclic AMP, and PKA Inhibition of Class II Major Histocompatibility Complex Expression in Monocytic Lines

Guoxuan Li,1,2 Jonathan A. Harton,1,2 Xinsheng Zhu,1,3 and Jenny P.-Y. Ting1,2,*

Lineberger Comprehensive Cancer Center,1 Department of Microbiology and Immunology,2 and Program in Oral Biology,3 University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295

Received 11 December 2000/Returned for modification 22 January 2001/Accepted 23 April 2001

Prostaglandins, pleiotropic immune modulators that induce protein kinase A (PKA), inhibit gamma interferon induction of class II major histocompatibility complex (MHC) genes. We show that phosphorylation of CIITA by PKA accounts for this inhibition. Treatment with prostaglandin E or 8-bromo-cyclic AMP or transfection with PKA inhibits the activity of CIITA in both mouse and human monocytic cell lines. This inhibition is independent of other transcription factors for the class II MHC promoter. These same treatments also greatly reduced the induction of class II MHC mRNA by CIITA. PKA phosphorylation sites were identified using site-directed mutagenesis and phosphoamino acid analysis. Phosphorylation at CIITA serines 834 and 1050 accounts for the inhibitory effects of PKA on CIITA-driven class II MHC transcription. This is the first demonstration that the posttranslational modification of CIITA mediates inhibition of class II MHC transcription.

* Corresponding author. Mailing address: CB#7295, Lineberger Comprehensive Cancer Center, Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295. Phone: (919) 966-5538. Fax: (919) 966-3015. E-mail: panyun{at}med.unc.edu.

Molecular and Cellular Biology, July 2001, p. 4626-4635, Vol. 21, No. 14
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.14.4626-4635.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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