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J. Biol. Chem., Vol. 281, Issue 52, 39963-39970, December 29, 2006

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Sequential Modifications in Class II Transactivator Isoform 1 Induced by Lipopolysaccharide Stimulate Major Histocompatibility Complex Class II Transcription in Macrophages^*

Gorazd Drozina, Jiri Kohoutek, Tadashi Nishiya^¶, and B. Matija Peterlin¹

From the Departments of Medicine, Microbiology and Immunology, Rosalind Russell Medical Research Center, University of California San Francisco, San Francisco, California 94143, the Division of Gastroenterology, Department of Internal Medicine, University Medical Center Ljubljana, Japljeva 2, 1000 Ljubljana, Slovenia, and the ^¶George Williams Hooper Foundation and the Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California 94143

By presenting antigenic peptides on major histocompatibility complex class (MHC) II determinants to CD4⁺ T cells, macrophages help to direct the establishment of adaptive immunity. We found that in these cells, lipopolysaccharide stimulates the expression of MHC II genes via the activation of Erk1/2, which is mediated by Toll-like receptor 4. Erk1/2 then phosphorylates the serine at position 357, which is located in a degron of CIITA isoform 1 that leads to its monoubiquitylation. Thus modified, CIITA isoform 1 binds P-TEFb, which mediates the elongation of RNA polymerase II and co-transcriptional processing of nascent transcripts. This induction leads to the expression of MHC II genes. Subsequent polyubiquitylation results in the degradation of CIITA isoform 1. Thus, the signaling cascade from Toll-like receptor 4 to CIITA isoform 1 represents one connection between innate and adaptive immunity in macrophages.

Received for publication, September 5, 2006 , and in revised form, November 2, 2006.

^* This work was funded by National Institutes of Health Grant R01 AI050770 and a grant from the Nora Eccles Treadwell Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1, S2, and S3.

¹ To whom correspondence should be addressed: Box 0703 UCSF, 3rd and Parnassus Aves., San Francisco, CA 94143-0703. Tel.: 415-502-1905; Fax: 415-502-1901; E-mail: matija.peterlin{at}ucsf.edu.

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