KAPtain in charge of multiple missions: Emerging roles of KAP1

Abstract

KAP1/TRIM28/TIF1β was identified nearly twenty years ago as a universal transcriptional co-repressor because it interacts with a large KRAB-containing zinc finger protein (KRAB-ZFP) transcription factor family. Many studies demonstrate that KAP1 affects gene expression by regulating the transcription of KRAB-ZFP-specific loci, trans-repressing as a transcriptional co-repressor or epigenetically modulating chromatin structure. Emerging evidence suggests that KAP1 also functions independent of gene regulation by serving as a SUMO/ubiquitin E3 ligase or signaling scaffold protein to mediate signal transduction. KAP1 is subjected to multiple post-translational modifications (PTMs), including serine/tyrosine phosphorylation, SUMOylation, and acetylation, which coordinately regulate KAP1 function and its protein abundance. KAP1 is involved in multiple aspects of cellular activities, including DNA damage response, virus replication, cytokine production and stem cell pluripotency. Moreover, knockout of KAP1 results in embryonic lethality, indicating that KAP1 is crucial for embryonic development and possibly impacts a wide-range of (patho)physiological manifestations. Indeed, studies from conditional knockout mouse models reveal that KAP1-deficiency significantly impairs vital physiological processes, such as immune maturation, stress vulnerability, hepatic metabolism, gamete development and erythropoiesis. In this review, we summarize and evaluate current literatures involving the biochemical and physiological functions of KAP1. In addition, increasing studies on the clinical relevance of KAP1 in cancer will also be discussed.

Keywords: Chromatin remodeling; KRAB domain-associated protein 1; KRAB-containing zinc finger protein; Post-translational modification; Transcriptional co-repressor.

Figure 1

KRAB domain-associated protein 1 is involved in multiple aspects of cellular physiology. Neurology: Kap1 knockout in mouse forebrain induces higher level of anxiety-like behavior. Developmental Biology: Several conditional kap1 deletions impair normal cell development including embryonic stem cell (ESC) differentiation, spermatogenesis, erythropoiesis, and the development of T-cell and B-cell. Immunology: KAP1 is involved in immune responses by regulating T/B cell activity and immune tolerance. Virology: KAP1 is critical to suppress retroviral activation and prevent HIV integration. Cancer Biology: KAP1 is positively or negatively correlated with prognosis in different cancer types. The roles of KAP1 in maintaining genome stability, mediating DNA damage response and affecting cell proliferation in vitro imply its potential roles during tumorigenesis.

Figure 2

KAP1 structure, post-translational modifications and interacting proteins. KAP1 has multi-domains for protein-protein interaction and post-translational modification. RBCC: RING-B1-B2-coiled-coil; TSS: TIF signature sequence; HP1 BD: HP1 binding domain; PHD: Plant homeo domain. Numbers represent the sequence of amino acids; Blue: SUMOylation sites; Red: Serine phosphorylation sites targeted by the indicated kinases (shown in red) or antagonized by phosphatases (shown in green); Orange: Tyrosine phosphorylation sites targeted by the indicated kinase family; KLIYF: PP1 binding site; PxVxL: HP1 binding site; Dotted lines: Protein-protein interaction; SFKs: Src family kinases; HP1: Heterochromatin-associated protein 1; ATM: Ataxia-telangiectasia mutated; PP1: Protein phosphatase 1; CHD3/NuRD: Chromodomain helicase DNA binding protein 3/nucleosome remodeling deacetylase; HDAC: Histone deacetylase.