Exploration of Targeted Anti-tumor Therapy

Table 1

Examples of ISGylation target proteins

Protein	ISGylation sites	E3 ligase	Activity	Effect of ISGylation on stability or activity	Reference
TRIM25	K117	TRIM25	E3 ISG15 ligase	Reduces the TRIM25 activity as an E3 ligase for ISG15	[17]
TRIM25	K117	TRIM25	E3 ubiquitin ligase	ND	[17]
Filamin B	K2467	ND	Scaffold protein	Affects interactions, reducing MAPK and JNK signaling	[18]
PARK	K349 K369	HERC5	E3 ubiquitin ligase	Increases its E3 ubiquitin activity Increases its cytoprotective effect	[19]
ΔNp63α	K139 K324	ND	Pro-tumor	Reduces ΔNp63α activity and promotes tumor growth	[20]
BECN1	K117 K263 K265 K266	HERC5	Autophagy-associated protein	Inhibits autophagy and promotes antiviral responses	[15]
4EHP	K134 K222	HHARI	Translation repressor (cap-binding)	Increases the cap structure-binding activity Inhibits the translation of mRNAs	[21]
14-3-3σ	ND	TRIM25	Associated protein with oncogenic signaling	ND	[22]
14-3-3ζ	ND	ND	Oncogenic signaling	Affects the stability of 14-3-3ζ Loss of USP18 destabilizes 14-3-3ζ protein, repressing lung cancer metastasis	[23]
PCNA	K164 K168	TRIM25	DNA replication and repair	Terminates error-prone TLS Prevents excessive mutagenesis	[24]
p53	Multiple sites	HERC5	Tumor suppressor	Inactivates p53 tumor suppressor	[16]
	Multiple sites	HERC5		Facilitates degradation of misfolded p53 (via 20S proteasome)	[14]
	K291 K292	TRIM25		Increases the transcriptional activity of p53	[25]
HIF-1α	Multiple sites	HERC5	Transcription factor	Reduces HIF-1α levels Reduces HIF-1α-induced expression	[26]
β-catenin	ND	HERC5	Co-factor	Increases the degradation of β-catenin (ISGylation-dependent ubiquitination) in colon cancer cells	[27, 28]
FOXO3A	ND	ND	Transcription factor	Increases degradation of FOXO3A in human lung fibroblasts	[29]
PTEN	C-terminus	ND	Tumor suppressor (phosphatase)	Decreases the stability of PTEN, reducing its tumor suppressor activity, but USP18 stabilizes PTEN protein	[30]
EMD	K37	ND	Pro-tumor	Inhibits the EMD ubiquitination, increasing its stability and pro-tumor activity	[31]
YAP	K497	HERC5	Pro-tumor Co-factor	Reduces the degradation of YAP, increasing its pro-tumor activity	[32]
Ki-ras (GDI2)	Several sites	ND	Pro-tumor	Increases the endocytic recycling of the EGFR and sustained Akt signaling Breast cancer progression	[33]
OCT4	K284	ND	Transcription factor	Enhances the stability of OCT4 Promotes glioma cell stemness	[34]

Return to article view

ND: not determined; MAPK: mitogen-activated protein kinase; JNK: c-Jun N-terminal kinase; PARK: parkin; ΔNp63α: alternative splice variant of phosphoprotein 63; BECN1: beclin 1; 4EHP: eukaryotic translation initiation factor 4E homologous protein; 14-3-3σ: stratifin; PCNA: proliferating cell nuclear antigen; TLS: translesion DNA synthesis; p53: phosphoprotein 53; HIF-1α: hypoxia-inducible factor 1 subunit α; FOXO3A: forkhead box O3A; PTEN: phosphatase and tensin homolog; EMD: skeletal protein emerin; YAP: Yes-associated protein; EGFR: epidermal growth factor receptor; Akt: Akt kinase; Ki-ras: KRAS proto-oncogene, GTPase; GDI2: guanosine diphosphate (GDP) dissociation inhibitor 2; OCT4: POU class 5 homeobox 1 (also known as POU5F1)