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Human UBA7/UBE1L (UniProt P41226) is the E1 activating enzyme of the ISG15
conjugation (ISGylation) pathway and is the only ISG15-activating enzyme
identified to date.
"UBA7/UBE1L is the **E1 enzyme** that performs the **first step** in the ISGylation cascade: it activates ISG15 for transfer to the E2 enzyme. A recent primary study explicitly states that **UBA7/UBE1L encodes the only ISG15-activating enzyme identified to date**."
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UBA7 follows the canonical E1 mechanism: ATP-dependent adenylation of the ISG15
C-terminus, formation of an E1~ISG15 thioester at the catalytic cysteine, then
transthiolation to the cognate E2 UBE2L6 (UbcH8).
"1. **ATP-dependent adenylation** of the ISG15 C-terminus (forming an ISG15 adenylate intermediate).
2. Formation of an **E1~ISG15 thioester** at the UBA7 catalytic cysteine.
3. **Transthiolation (E1→E2 transfer)** to the catalytic cysteine of the cognate E2, **UBE2L6 (UbcH8)**, generating **UBE2L6~ISG15**, which then supports E3-mediated isopeptide bond formation on substrates."
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UBA7 is a dedicated ISG15 E1, distinct from the ubiquitin E1 UBA1; specificity
is enforced by defined ISG15 and UBE2L6 interface determinants (ISG15 C-lobe
engagement, N-lobe dispensability for thioester formation, and an ISG15 Thr125
patch that limits mis-activation by UBA1).
"UBA7 is widely treated as an **ISG15-dedicated E1**, contrasted with the ubiquitin E1 UBA1 in parallel biochemical contexts."
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The canonical cognate E2 is UBE2L6 (UbcH8); downstream ISG15 E3 ligases include
HERC5 (dominant human E3), TRIM25/EFP, and ARIH1. ISGylation is reversible, with
USP18 as the major human deISGylase.
"**UBE2L6 / UbcH8** is the canonical cognate E2 for ISG15 transfer from UBA7."
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HERC5 is emphasized as the dominant human ISG15 E3 ligase; loss of HERC5 markedly
reduces observable ISGylation.
"**HERC5** is emphasized as the dominant human ISG15 E3 ligase in reviews (loss of HERC5 markedly reduces observable ISGylation), and it is central in viral restriction examples."
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UBA7 expression is interferon-inducible but can be negatively regulated; in some
cell contexts (e.g. HCT116), early USP18 expression after interferon suppresses
UBA7 expression and limits ISGylation, and USP18 depletion restores
IFN-dependent UBA7/UBE2L6 expression.
"in some contexts, **USP18 early expression after interferon can suppress UBA7 expression**, limiting ISGylation despite interferon responsiveness (shown in HCT116 cells; USP18 depletion restored interferon-dependent expression of UBA7 and UBE2L6/UBCH8 and rescued ISGylation)."
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UBA7 function is intracellular and consistent with cytosolic innate immune
signaling; however, direct compartment-resolved localization data for UBA7
itself are limited in the recent literature.
"within the retrieved excerpts, **direct experimental statements localizing UBA7 itself to a specific compartment (cytosol vs nucleus; organelle association) are limited**."
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UBA7-dependent ISGylation supports antiviral innate immunity: it restricts
SARS-CoV-2 via HERC5-mediated ISGylation of the nucleocapsid (N) protein
(impairing N oligomerization and viral RNA synthesis), and UBA7 deficiency
attenuates cGAS-STING antiviral gene expression while UBA7 knockdown facilitates
HSV-1 infection.
"**HERC5-mediated ISGylation of N** disrupts N oligomerization/assembly and inhibits viral RNA synthesis, while the viral **PLpro/NSP3** counters by deISGylation"
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In UBA7-null epithelial cells, dsRNA (Poly I:C)-triggered NF-kB activation and
IFNB1 induction are markedly reduced, linking UBA7-dependent ISGylation to
dsRNA-induced inflammatory signaling.
"loss of ISGylation (UBA7-null) reduced Poly I:C-triggered NF-κB activation (**p-RELA ≈30% of parental** in one summary) and reduced Poly I:C-induced **IFNB1 transcript induction to ≈50% of parental**"