KAP1/TRIM28: Transcriptional Activator and/or Repressor of Viral and Cellular Programs?

Abstract

Several transcriptional and epigenetic regulators have been functionally linked to the control of viral and cellular gene expression programs. One such regulator is Krüppel-associated box (KRAB)-associated protein 1 (KAP1: also named TRIM28 or TIF1β), which has been extensively studied in the past three decades. Here we offer an up-to date review of its various functions in a diversity of contexts. We first summarize the discovery of KAP1 repression of endogenous retroviruses during development. We then deliberate evidence in the literature suggesting KAP1 is both an activator and repressor of HIV-1 transcription and discuss experimental differences and limitations of previous studies. Finally, we discuss KAP1 regulation of DNA and RNA viruses, and then expand on KAP1 control of cellular responses and immune functions. While KAP1 positive and negative regulation of viral and cellular transcriptional programs is vastly documented, our mechanistic understanding remains narrow. We thus propose that precision genetic tools to reveal direct KAP1 functions in gene regulation will be required to not only illuminate new biology but also provide the foundation to translate the basic discoveries from the bench to the clinics.

Trim28 plays an indispensable role in maintaining functions and transcriptional integrity of hematopoietic stem cells

“…Self-renewal, quiescence and differentiation of HSCs are governed mainly by the spatiotemporal expression of transcription factors 44,45 . Recent studies established that Trim28 has dual functions, as both an activator and a repressor, in regulating transcription 13 . To study if Trim28 deficiency leads to altered expression levels of transcription factors that promote HSC self-renewal and/or myeloid differentiation, we performed gene expression studies.…”

“…Trim28 has been implicated in a variety of physiologic and pathophysiologic processes including immune regulation, viral pathogenesis, cancer, tumor microenvironment and epithelial-to-mesenchymal transition 12,13 . Within the immune system, functions of Trim28 has been established in adaptive immune cells, both in B- 30 and T- 31–33 lineage cells.…”

“…Emerging studies have unequivocally established that Trim28 is a highly versatile multidomain protein 12 with pleiotropic functions. Despite being recognized as a powerful suppressor of transcription 50 , Trim28 has been shown to function as a transcriptional activator 13 . Even though Trim28 has been shown to bind promoter/regulatory regions of over 3,000 genes 27 , protein-protein interactions have been identified to play a central role in the transcriptional regulation function of Trim28 51 .…”

“…Recent studies from our lab established that a deficiency of A20 (a ubiquitin editing enzyme) causes severe HSC defects and functions, which ultimately leads to pancytopenia and premature death 37,58,59 . Interestingly, Trim28 protein possesses a RING finger domain and has been identified to exert E3 ubiquitin ligase functions on substrates including p53, AMPK and CDK9 proteins 13,60 . However, to date, the E3 ligase functions of Trim28 in HSCs remain largely unidentified.…”

“…Trim proteins play pivotal roles in transcriptional regulation, cell proliferation, apoptosis, autophagy, DNA repair and oncogenesis through their unique capacities to perform dual functions as E3 ubiquitin ligases and transcriptional repressors/activators 9–11 . Indeed, deregulated expression of Trim family of genes causes several human diseases and disorders, such as cancer, immunological diseases, and developmental disorders 7,12,13 .…”