Vogel Jodi L, Kristie Thomas M
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4-131, 4 Center Drive, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2006 May 2;103(18):6817-22. doi: 10.1073/pnas.0602109103. Epub 2006 Apr 19.
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.
有限的蛋白水解加工是一种重要的转录调控机制。在各种情况下，蛋白水解作用控制着重要转录因子的胞质到核的转运，或者去除结构域以产生具有改变活性的因子。转录共激活因子宿主细胞因子1（HCF-1）在一个由20个氨基酸重复序列组成的独特结构域内进行蛋白水解加工。一个或多个重复序列内的位点特异性切割产生了一系列氨基末端和羧基末端亚基，它们仍然紧密结合。然而，HCF-1加工的后果尚未明确。在这项研究中，确定了HCF-1加工结构域与包括转录共激活因子/共抑制因子四又二分之一LIM结构域2（FHL2）在内的几种蛋白质相互作用。对这种相互作用的分析揭示了该加工结构域重复序列内序列和上下文决定因素的特异性。在细胞中，FHL2仅与未加工的共激活因子相互作用，并共同刺激HCF-1依赖的靶基因的转录。HCF-1与FHL2的功能相互作用支持了一种模型，即位点特异性蛋白水解调节HCF-1与蛋白质伙伴的相互作用，从而可以调节这种共激活因子的活性。这种模式扩展了有限蛋白水解加工作为基因转录调控机制的生物学意义。
