Site-specific proteolysis of the transcriptional coactivator HCF-1 can regulate its interaction with protein cofactors

Jodi L. Vogel, and Thomas M. Kristie^*

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4-131, 4 Center Drive, Bethesda, MD 20892

Received for publication January 15, 2006.

Abstract: Limited proteolytic processing is an important transcriptional regulatory mechanism. In various contexts, proteolysis controls the cytoplasmic-to-nuclear transport of important transcription factors or removes domains to produce factors with altered activities. The transcriptional coactivator host cell factor-1 (HCF-1) is proteolytically processed within a unique domain consisting of 20-aa reiterations. Site-specific cleavage within one or more repeats generates a family of amino- and carboxyl-terminal subunits that remain tightly associated. However, the consequences of HCF-1 processing have been undefined. In this study, it was determined that the HCF-1-processing domain interacts with several proteins including the transcriptional coactivator/corepressor four-and-a-half LIM domain-2 (FHL2). Analysis of this interaction has uncovered specificity with both sequence and context determinants within the reiterations of this processing domain. In cells, FHL2 interacts exclusively with the nonprocessed coactivator and costimulates transcription of an HCF-1-dependent target gene. The functional interaction of HCF-1 with FHL2 supports a model in which site-specific proteolysis regulates the interaction of HCF-1 with protein partners and thus can modulate the activity of this coactivator. This paradigm expands the biological significance of limited proteolytic processing as a regulatory mechanism in gene transcription.

Key Words: FHL2 • transcription • herpes simplex virus • protein interactions

Author contributions: J.L.V. and T.M.K. designed research; J.L.V. performed research; J.L.V. and T.M.K. analyzed data; and T.M.K. wrote the paper.

Conflict of interest statement: No conflicts declared.

*To whom correspondence should be addressed. E-mail: tkristie{at}nih.gov

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