KAPtain in charge of multiple missions: Emerging roles of KAP1

Table 1 Chromatin-associated factors/chromatin-remodeling enzymes interacting with KAP1

Chromatin-associated factors/chromatin-remodeling enzymes	Consequences of binding with KAP1	Ref.
HP1	HP1-KAP1 interaction leads to transcriptional repression and has an essential role in development and cell differentiation. Phosphorylation at Ser-473 or Tyr-449, 458, 517 of KAP1 inhibits its interaction with HP1.	[5,6,33,43,46,53,94-97,105]
SETDB1	KAP1 binds to SETDB1 through SUMO:SIM interaction to methylate H3K9 at gene regulatory regions to achieve gene silencing.	[9,15,16,109]
N-CoR	N-CoR represses basal transcription by the recruitment of HDACs to deacetylate histones. KAP1 is involved in N-CoR-1 complex to mediate transcriptional repression.	[7]
CHD3 (Mi-2α)/NuRD	NuRD complex mediates chromatin remodelling and histone deacetylation via CHD3 (Mi-2α) and HDACs, respectively. KAP1 interacts with NuRD complex via PHD and bromodomain to alter the chromatin structure.	[8,21,37]
HDAC1	KAP1-HDAC1 complex interaction not only regulates histone modification but also non-histone protein deacetylation to exert a variety of different functions (also shown in Table 2).	[113]
SMARCAD1	SMARCAD1 mediates histone deacetylation and associates with KAP1-HDAC1 complex to regulate chromatin marks.	[58]
DNMT	KAP1 associates with DNMT to maintain DNA methylation at imprinting control region (also shown in Table 2).	[59,61]

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; N-CoR: Nuclear co-repressor; SETDB1: Bifurcated 1; DNMT: DNA methyltransferase.

Table 2 Transcription factors involved in KAP1-regulated gene expression

Transcription factor	KAP1 function	Ref.
Myc	KAP1 is involved in MM-1 and HDAC1 complex to suppress c-Myc transcription activity	[10,11]
ZNF160	KAP1 interacts with ZNF160 and recruits HDAC to downregulate TLR4 in intestinal epithelial cells	[79]
Oct3/4	KAP1 is potentially involved in regulating pluripotency of embryonic stem cells	[78]
E2F1	KAP1 suppresses E2F1 transcriptional activity and inhibits E2F1 acetylation in an HDAC1 dependent manner	[13]
p53	KAP1 is associated with MDM2-p53-HDAC1 complex and inhibits p53 acetylation and promotes p53 degradation	[75]
p53	MAGE proteins stabilize KAP1-p53 complex to decrease acetylation and promote degradation of p53	[80]
p53	KAP1 ubiquitinates p53 for proteasome degradation	[23]
IRF7	KAP1 sumolyates IRF7 and suppresses IRF7 transcriptional activity in IFN production	[24]
ZBRK1	KAP1 interacts with ZBRK1 to repress Gadd45α and p21 gene expression	[16,17,69]
HIF-1α	VHLaK potentially recruits KAP1 to HIF-1α complex to suppress HIF-1α downstream gene expression	[72]
Nrf2	KAP1 interacts with Nrf2 and facilitates Nrf2 transactivation activity	[76]
STAT3	KAP1 interacts with STAT3 to suppress STAT3 transcriptional activity	[82]
STAT1	KAP1 interacts with STAT1 to suppress STAT1 transcriptional activity	[50]
ZNF689	ZNF689 potentially recruits KAP1 to suppress autophagy-gene-targeting miRNAs	[71]
FOXP3	KAP1 is recruited by FIK in FOXP3-FIK-KAP1 complex to suppress FOXP3-target genes	[74]
NFκB	KAP1 is associated with NFκB and negatively regulates it acetylation and transcriptional activity	[51]
SRY	KAP1 is recruited by KRAB-O to SRY binding sites for gene regulation	[68,73]
ZFP57	ZFP57 and KAP1 are associated with NP95-DNMT complex for maintaining DNA methylation at imprinting control region	[59,61,62]

VHLaK: VHL-associated KRAB-A domain-containing protein; HDAC: Histone deacetylase; DNMT: DNA methyltransferase.

Table 3 Mouse models illustrating the physiological functions of Kap1

Animal model	Phenotype	Ref.
Kap1 knockout mice	Embryonic lethal prior to gastulation	[19]
Hemato-specific Kap1 knockout mice	Impaired erythropoiesis	[71,100]
T-cell-specific Kap1 knockout mice	Defective T-cell differentiation	[48,98]
B-cell-specific Kap1 knockout mice	Defective B-cell differentiation	[99]
Tamoxifen-inducible-germ cell-lineage-specific Kap1 depletion mice	Impaired spermatogenesis	[101]
Liver-specific Kap1 knockout mice	Male-predominant steatosis and hepatic adenoma	[120]
Kap1 knockout in mice forebrain	Anxiety-like-behavior and cognitive impairments	[103]