Gene interactions and pathways from curated databases and text-mining
Proc Natl Acad Sci U S A 2005, PMID: 16009940

Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways.

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

  • 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)
  • IRef Biogrid Interaction: ACOT8 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — TXNRD1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: HSPA1A — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: SF3B4 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — PALLD (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CCT4 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: GPI — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — DYRK1A (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: GNB2L1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PSMA7 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — SERPINB5 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — WARS (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: WDR33 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — PTBP1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — PLS3 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TAGLN — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: HNRNPA2B1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TOP2A — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: HNRNPK — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: LMAN2 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — HELZ2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CIRH1A — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TARS — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: MYH9 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — PKM (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PRDX1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — CBX4 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: STAT1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: YTHDF3 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ATIC — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: SNRNP200 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — DEPDC7 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TAF2 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: FASN — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PPP1R10 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ELAVL1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CLIC1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: XRCC6 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — SMAD4 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: RPL24 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — ACLY (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — GANAB (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — RAN (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — ANXA2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: DNAJB4 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — ANXA5 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: VIM — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — CFL1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PFN1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: IFIT5 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: TMOD3 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — HSPA8 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CCNL1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — PLOD1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: LAP3 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — EZR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ATP5A1 — ISG15 (physical association, affinity chromatography technology)
  • 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)
  • IRef Biogrid Interaction: ISG15 — ATXN2L (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: MX1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CHD1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: NUP43 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — HSP90AB1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — RBBP4 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: LDHA — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: PLS1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — PLEC (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — AHNAK (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — HSPD1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: RPS27A — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — HSP90AA1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — SIN3A (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: IFIT3 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: UBE2N — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — CALD1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — GSR (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — FLNA (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: HERC5 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CCT2 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — EIF2AK2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: FARS2 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ATXN2 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — UBAP2L (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: EEF2 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ARID5B — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — HNRNPL (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: G3BP1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: MEPCE — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: QTRTD1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: LMNA — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — IFIT2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CHMP5 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — YTHDC1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — SERBP1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — SENP1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — GDI2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — EIF4G1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — DDX17 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: CSNK2A1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: NFIX — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — OGDH (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — CCT3 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ZC3HAV1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — MAP4 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — NACA (physical association, affinity chromatography technology)
  • 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)
  • IRef Biogrid Interaction: ISG15 — ABCF2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: EPPK1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — FLNB (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: IFIT1 — ISG15 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — DDX58 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: ISG15 — ENO1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: UBA7 — ISG15 (physical association, affinity chromatography technology)
  • Reactome Reaction: UBE2L6 → HERC5 (reaction)
  • Reactome Reaction: UBE2L6 → ISG15 (reaction)
  • Reactome Reaction: UBE2L6 → FLNB (reaction)
  • Reactome Reaction: JAK1 → HERC5 (reaction)
  • Reactome Reaction: HERC5 → STAT1 (reaction)
  • Reactome Reaction: ARIH1 → JAK1 (reaction)
  • Reactome Reaction: UBE2L6 → STAT1 (reaction)
  • Reactome Reaction: FLNB → HERC5 (reaction)
  • Reactome Reaction: MAPK3 → ISG15 (reaction)
  • Reactome Reaction: IFIT1 → ISG15 (reaction)
  • 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