Proc Natl Acad Sci U S A 2005,
PMID: 16009940
Zhao, Chen; Denison, Carilee; Huibregtse, Jon M; Gygi, Steven; Krug, Robert M
IFN-alpha/beta plays an essential role in innate immunity against viral and bacterial infection. Among the proteins induced by IFN-alpha/beta are the ubiquitin-like ISG15 protein and its E1- (Ube1L) and E2- (UbcH8) conjugating enzymes, leading to the conjugation of ISG15 to cellular proteins. It is likely that ISG15 conjugation plays an important role in antiviral response because a human virus, influenza B virus, inhibits ISG15 conjugation. However, the biological function of ISG15 modification remains unknown, largely because only a few human ISG15 target proteins have been identified. Here we purify ISG15-modified proteins from IFN-beta-treated human (HeLa) cells by using double-affinity selection and use mass spectroscopy to identify a large number (158) of ISG15 target proteins. Eight of these proteins were subjected to further analysis and verified to be ISG15 modified in IFN-beta-treated cells, increasing the likelihood that most, if not all, targets identified by mass spectroscopy are bona fide ISG15 targets. Several of the targets are IFN-alpha/beta-induced antiviral proteins, including PKR, MxA, HuP56, and RIG-I, providing a rationale for the inhibition of ISG15 conjugation by influenza B virus. Most targets are constitutively expressed proteins that function in diverse cellular pathways, including RNA splicing, chromatin remodeling/polymerase II transcription, cytoskeleton organization and regulation, stress responses, and translation. These results indicate that ISG15 conjugation impacts nuclear as well as cytoplasmic functions. By targeting a wide array of constitutively expressed proteins, ISG15 conjugation greatly extends the repertoire of cellular functions that are affected by IFN-alpha/beta.
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Text Mining Data
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Manually curated Databases
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IRef Biogrid Interaction:
DDB2
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
CLK1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
IQGAP1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
ATP5B
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
RDH11
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
PGK1
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
PGD
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
LGMN
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
DNAJB1
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
FAM120C
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ZC3H15
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
DDX42
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
EEF1G
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ZNF281
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
RBM15B
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
EEF1A2
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
MSN
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
RPL27A
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
PLOD3
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
PAFAH1B1
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
CLTC
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
VCP
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
ACTN4
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
TKT
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
HNRNPU
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
UBE2L6
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ACTA1
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
GBP1
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
FUBP3
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
XRCC5
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
PHGDH
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
ANXA3
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ACOT8
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
TXNRD1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
HSPA1A
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
SF3B4
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
PALLD
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
CCT4
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
GPI
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
DYRK1A
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
GNB2L1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
PSMA7
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
SERPINB5
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
WARS
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
WDR33
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
PTBP1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
PLS3
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
TAGLN
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
HNRNPA2B1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
TOP2A
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
HNRNPK
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
LMAN2
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
HELZ2
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
CIRH1A
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
TARS
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
MYH9
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
PKM
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
PRDX1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
CBX4
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
STAT1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
YTHDF3
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ATIC
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
SNRNP200
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
DEPDC7
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
TAF2
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
FASN
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
PPP1R10
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ELAVL1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
CLIC1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
XRCC6
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
SMAD4
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
RPL24
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
ACLY
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
GANAB
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
RAN
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
ANXA2
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
DNAJB4
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
ANXA5
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
VIM
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
CFL1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
PFN1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
IFIT5
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
TMOD3
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
HSPA8
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
CCNL1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
PLOD1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
LAP3
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
EZR
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ATP5A1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
AAAS
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
SF3A2
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
WIBG
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
GSTP1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
ATXN2L
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
MX1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
CHD1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
NUP43
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
HSP90AB1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
RBBP4
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
LDHA
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
PLS1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
PLEC
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
AHNAK
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
HSPD1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
RPS27A
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
HSP90AA1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
SIN3A
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
IFIT3
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
UBE2N
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
CALD1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
GSR
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
FLNA
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
HERC5
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
CCT2
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
EIF2AK2
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
FARS2
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ATXN2
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
UBAP2L
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
EEF2
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ARID5B
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
HNRNPL
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
G3BP1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
MEPCE
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
QTRTD1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
LMNA
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
IFIT2
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
CHMP5
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
YTHDC1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
SERBP1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
SENP1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
GDI2
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
EIF4G1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
DDX17
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
CSNK2A1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
NFIX
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
OGDH
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
CCT3
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ZC3HAV1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
MAP4
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
NACA
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
ALDOA
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
ACTN1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
WDR1
—
ISG15
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
MYOF
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
ABCF2
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
EPPK1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
FLNB
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
IFIT1
—
ISG15
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
ISG15
—
DDX58
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ISG15
—
ENO1
(physical association, affinity chromatography technology)
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IRef Biogrid Interaction:
UBA7
—
ISG15
(physical association, affinity chromatography technology)
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Reactome Reaction:
UBE2L6
→
HERC5
(reaction)
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Reactome Reaction:
UBE2L6
→
ISG15
(reaction)
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Reactome Reaction:
UBE2L6
→
FLNB
(reaction)
-
Reactome Reaction:
JAK1
→
HERC5
(reaction)
-
Reactome Reaction:
HERC5
→
STAT1
(reaction)
-
Reactome Reaction:
ARIH1
→
JAK1
(reaction)
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Reactome Reaction:
UBE2L6
→
STAT1
(reaction)
-
Reactome Reaction:
FLNB
→
HERC5
(reaction)
-
Reactome Reaction:
MAPK3
→
ISG15
(reaction)
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Reactome Reaction:
IFIT1
→
ISG15
(reaction)
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Reactome Reaction:
PLCG1
→
HERC5
(reaction)
-
Reactome Reaction:
ARIH1
→
FLNB
(reaction)
-
Reactome Reaction:
ARIH1
→
UBE2E1
(reaction)
-
Reactome Reaction:
ISG15
→
STAT1
(reaction)
-
Reactome Reaction:
PLCG1
→
UBE2L6
(reaction)
-
Reactome Reaction:
UBE2E1
→
ISG15
(reaction)
-
Reactome Reaction:
PLCG1
→
ISG15
(reaction)
-
Reactome Reaction:
ISG15
→
ISG15
(reaction)
-
Reactome Reaction:
IFIT1
→
HERC5
(reaction)
-
Reactome Reaction:
ARIH1
→
MAPK3
(reaction)
-
Reactome Reaction:
MAPK3
→
HERC5
(reaction)
-
Reactome Reaction:
ISG15
→
FLNB
(reaction)
-
Reactome Reaction:
IFIT1
→
UBE2L6
(reaction)
-
Reactome Reaction:
ARIH1
→
PLCG1
(reaction)
-
Reactome Reaction:
ARIH1
→
STAT1
(reaction)
-
Reactome Reaction:
JAK1
→
UBE2L6
(reaction)
-
Reactome Reaction:
UBE2E1
→
UBE2L6
(reaction)
-
Reactome Reaction:
HERC5
→
HERC5
(reaction)
-
Reactome Reaction:
UBE2E1
→
HERC5
(reaction)
-
Reactome Reaction:
ARIH1
→
UBE2L6
(reaction)
-
Reactome Reaction:
ARIH1
→
IFIT1
(reaction)
-
Reactome Reaction:
MAPK3
→
UBE2L6
(reaction)
-
Reactome Reaction:
ISG15
→
HERC5
(reaction)
-
Reactome Reaction:
UBE2L6
→
UBE2L6
(reaction)
-
Reactome Reaction:
ARIH1
→
HERC5
(reaction)
-
Reactome Reaction:
JAK1
→
ISG15
(reaction)
-
Reactome Reaction:
ARIH1
→
ISG15
(reaction)
-
Reactome Reaction:
ARIH1
→
ARIH1
(reaction)
In total, 184 gene pairs are associated to this article in curated databases