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Site-Specific Proteolysis of the Transcriptional Coactivator HCF-1 Can Regulate Its Interaction with Protein Cofactors

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Site-Specific Proteolysis of the Transcriptional Coactivator HCF-1 Can Regulate Its Interaction with Protein Cofactors 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 Communicated by Bernard Moss, National Institutes of Health, Bethesda, MD, March 15, 2006 (received for review January 15, 2006) Limited proteolytic processing is an important transcriptional reg- gene expression profiling studies (27) have indicated that HCF-1 ulatory mechanism. In various contexts, proteolysis controls the is a control component of cellular functions such as general cytoplasmic-to-nuclear transport of important transcription factors transcription, DNA replication-repair, mRNA processing, and or removes domains to produce factors with altered activities. The signal transduction. HCF-1 is also essential for multiple stages of transcriptional coactivator host cell factor-1 (HCF-1) is proteolyti- cell-cycle progression (28, 29), and this requirement may reflect cally processed within a unique domain consisting of 20-aa reiter- the protein’s broad transcriptional functions. ations. Site-specific cleavage within one or more repeats generates Proteolytic processing of HCF-1 is unique. The central region a family of amino- and carboxyl-terminal subunits that remain of the protein, the proteolytic processing domain (PPD), con- tightly associated. However, the consequences of HCF-1 processing tains a series of 20-aa reiterations (Fig. 1A). Autocatalytic have been undefined. In this study, it was determined that the cleavage of the 220-kDa precursor occurs within one or more of HCF-1-processing domain interacts with several proteins including these repeats to generate a family of 100- to 180-kDa amino- and the transcriptional coactivator͞corepressor four-and-a-half LIM do- carboxyl-terminal polypeptides (15). In contrast to the process- main-2 (FHL2). Analysis of this interaction has uncovered specificity ing of other transcription factors such as SREBP and ATF6, with both sequence and context determinants within the reitera- processing of HCF-1 appears to occur primarily in the nucleus tions of this processing domain. In cells, FHL2 interacts exclusively and can proceed such that a given HCF-1 molecule may be with the nonprocessed coactivator and costimulates transcription progressively cleaved at multiple reiterations (30). However, of an HCF-1-dependent target gene. The functional interaction of despite this processing, the resulting family of amino- and HCF-1 with FHL2 supports a model in which site-specific proteolysis carboxyl-terminal cleavage products remain tightly associated regulates the interaction of HCF-1 with protein partners and thus (31). Thus, the multisite nuclear processing and the association can modulate the activity of this coactivator. This paradigm ex- of the resulting subunits suggest that the cleavage may play a role pands the biological significance of limited proteolytic processing in the regulation of this coactivator. Recently it has been as a regulatory mechanism in gene transcription. demonstrated that processing may segregate the functions of HCF-1 in cell-cycle progression because HCF-1 amino-terminal FHL2 ͉ transcription ͉ herpes simplex virus ͉ protein interactions subunits promote the G0-to-G1 transition, whereas carboxyl- terminal subunits promote cytokinesis (29). However, the bio- ite-specific or limited proteolytic processing has emerged as logical consequences of the processing remain elusive. San important mechanism contributing to the regulation of In this study, it was determined that the PPD is not solely a basic cellular processes such as gene transcription, cell cycle target for processing but is also a domain involved in multiple progression, apoptosis, signal transduction, and differentiation. protein–protein interactions. One PPD-binding partner, FHL2, As a control mechanism for transcription of RNAPII-dependent is a member of the four-and-a-half LIM domain (FHL) family, genes, limited proteolysis has been shown to determine the which functions as a transcriptional coactivator͞corepressor nuclear transport of cytoplasmic or membrane-bound transcrip- (32–40). The interaction of the HCF-1 PPD with FHL2 reveals tion factors such as SREBP, CREB3, ATF6, Cubitus interrup- that this unique domain contains distinct specificities for protein tus, Tisp40, and Notch (1–8). In these cases, processing provides binding and that the HCF-1 reiterations are not equivalent. a mechanism to release sequestered factors to promote nuclear FHL2 selectively interacts with the uncleaved HCF-1 form and localization and affect the transcription of target genes. In other coactivates an HCF-1-dependent promoter, elucidating a mech- cases, exemplified by IRF2, C͞EBP␤, and Stats 3, 5, and 6, anism in which proteolytic processing can control specific HCF-1 BIOCHEMISTRY processing removes domains required for transcriptional activa- protein interactions and thus modulate the transcriptional po- tion, thus producing negative regulatory factors (9–11). Al- tential of the coactivator. though many of these processing events are means by which the cell may respond to stimuli, proteolysis of factors such as p53 and Results ͞ CDP Cut contribute to a program that modulates cell-cycle The HCF-1 PPD: Processing and Protein Interactions. As shown in Fig. progression (12, 13). 1A, the domains of the coactivator HCF-1 include (i) a kelch The transcriptional coactivator host cell factor-1 (HCF-1) domain that interacts with transcription factors (VP16, E2F4, undergoes a unique site-specific proteolytic processing (14–16). Krox20, CREB3, and Zhangfei) (20, 21, 41–43) and transcrip- The protein was originally identified as a component of the tional coactivators (PGC) (25); (ii) a basic region that interacts herpes simple virus (HSV) immediate-early (IE) gene enhancer complex (17), where it mediates the combinatorial transcrip- tional regulation of the viral IE genes (18). It has since been Conflict of interest statement: No conflicts declared. defined as a transcriptional coactivator for cellular factors such Freely available online through the PNAS open access option. as GABP, Sp1, E2F4, Krox20, CREB3, and Zhangfei (18–22). Abbreviations: HCF-1, host cell factor-1; HCF-1nc, noncleavable HCF-1; HSV, herpes simplex In addition, HCF-1 interactions with chromatin modification virus; IE, immediate-early; FHL, four-and-a-half LIM domain; PPD, proteolytic processing components (Set1͞Ash2 and PDCD2) (23, 24), other coactiva- domain. tors (PGC) (25), and mRNA splicing machinery (26) as well as *To whom correspondence should be addressed. E-mail: [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0602109103 PNAS ͉ May 2, 2006 ͉ vol. 103 ͉ no. 18 ͉ 6817–6822 Downloaded by guest on October 2, 2021 that the interaction of the HCF-1 PPD with FHL2 was specific, even to the point of discriminating between FHL2 and the highly related protein FHL3. Furthermore, because the protein was originally isolated using the HCF-1 PPD repeats 2 and 3, it was likely that the interaction was, at least in part, mediated by the HCF-1 repeats. Inherent Specificity for Protein Interactions Encoded Within the HCF-1 PPD. The HCF-1 PPD consists of six conserved reiterations (rpt 1–6), three interspersed divergent repeats (d1, d2, and d3), and a putative LXXLL coactivator motif (Fig. 1B). To define the interaction determinants within this reiterated domain, con- structs representing various configurations of the intact or proteolytically processed products were tested for interaction with the GST-FHL2 fusion protein (Fig. 1B). Deletion of either repeat 1, the amino-terminal consensus repeats (1–3), or the carboxyl-terminal consensus repeats (4–6) moderately impaired the interaction (2–6, 76%; d1–6, 52%; 1–d2, 73%), although deletion of the amino-terminal reiterations consistently im- pacted the interaction more severely than deletion of repeats 4–6. In contrast, deletion of the HCF-1 PPD region containing the divergent repeats d1–d2 and the LXXLL motif nearly abrogated the interaction (1–3͞4–6, 3%). Because deletion of this central region might alter the relative spacing of the remaining consensus reiterations, this region was replaced with an equivalent-sized protein segment derived from ␤-gal (1–2͞␤-gal͞4–6). This replacement resulted in some recovery of the HCF-1–FHL2 interaction (11%), suggesting that the con- Fig. 1. HCF-1–FHL2 interaction mediated by the central region of the PPD. figuration of the intact HCF-1 PPD was a consideration. How- (A) The HCF-1 PPD is shown relative to the amino-terminal (kelch and basic) and the carboxyl-terminal (TA, transactivation; FN3, fibronectin type III; NL, ever, alteration of the central repeat region (d1–d2–LXXLL) nuclear localization signal) domains. An alignment of the 20 amino acid still significantly impacted the HCF-1 PPD–FHL2 interaction. consensus repeats (blue ovals) and divergent repeats (red ovals) is shown. (B) Consistent with the suggestion that the central divergent repeats The HCF-1 PPD contains consensus repeats (blue ovals, 1–2–3, 4–5, and 6), represent the primary determinants for the FHL2–HCF-1 in- divergent repeats (red ovals, d1–d2 and d3), and an LXXLL motif (yellow teraction, deletion of d1–d2–LXXLL from constructs contain- circles, L). GST or GST-FHL2 fusion proteins (3 ␮g) were incubated with the ing either amino- or carboxyl-terminal repeats abrogated the illustrated
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