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.
Highlights
Several transcriptional and epigenetic regulators have been functionally linked to the control of viral and cellular gene expression programs
After this journeywe have learned thatKAP1regulates transcriptional repression and activation thereby contributing to multiple important phenotypes from the control of embryodevelopmentto the regulation of stem cell maintenance and differentiation repression
KAP1 inactivation triggers disease phenotypes such as embryonic lethality, cancer, and obesity. Besides these broad cellular functions and phenotypes, KAP1 has been linked to the control of viral expression either positively or negatively
Summary
One of the first viruses to be characterized as KAP1 regulated was the MLV retrovirus. The authors expressed wild-type KAP1 and the SUMO mutant in KAP1 knockout cells to show that SUMOylation is important for KAP1-mediated repression of ERVs and antiviral gene products, including genes related to innate immunity Another group studying highly pathogenic IAV found that KAP1 phosphorylation at S473 (pS473) (Figure 2A), not SUMOylation, was involved in regulating immune responses upon IAV infection (Krischuns et al, 2018). In 2021, Tovo et al conducted a clinical correlation study showing that children infected with SARS-CoV-2 had upregulated levels of KAP1 and SETDB1 along with type 1 interferon-stimulated genes, proposing that KAP1 may play a repressive role in infection (Tovo et al, 2021) In addition to this correlational study, another group found that KAP1 silencing using siRNA led to enhanced expression of ACE2, the SARS-CoV-2 receptor, in cancer cell models and primary human lung epithelial cells (Wang et al, 2021). The mechanism of action and whether KAP1 truly plays a repressive role in the SARS-CoV-2 infection remains unclear
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