IndraLab
Statements
sparser
"3D modelling of the STAT2-USP18 heterodimer showed both the amino acid residues, A219 and R148, to localize to the interface between STAT2 and USP18 (Fig. xref c), suggesting that the A219, like the R148, residue might play an essential role in mediating a STAT2-USP18 protein interaction."
sparser
"Collectively, the above data suggest a model in which the homozygous STAT2 p.(A219V) mutation disrupts the interaction of STAT2 with USP18, leading to a failure of negative feedback regulation of IFN-I signalling and prolonged IFNAR activation and enhanced ISG expression (Fig. xref )."
sparser
"In silico deep mutagenesis of the predicted STAT2-USP18 interface highlighted a further 3 amino acid residues (E144, D151, and R223) as critical to mediating this interaction (Fig. xref ), all clustering in the STAT2 CCD domain in close proximity to the described mutant A219 and R148 residues."
sparser
"R148 and A219 are located within the CCD domain of STAT2, critical to the interaction of STAT2 with USP18 and thus inhibition of IFN-I signalling [ xref ], with in silico deep mutagenesis of the predicted STAT2-USP18 interface highlighting a further 3 amino acid residues (E144, D151, and R223) as potentially critical to this interaction, and in which mutations might be expected to result in prolonged IFN-I signalling due to loss of negative regulation by STAT2-USP18."
sparser
"When co-immunoprecipitation assays were conducted with cell lysates containing FLAG-tagged USP18 and Myc-tagged STAT2, aa 1-112, 51-242, 1-242, and 243-312, but not aa 113-242 and 313-372 of USP18 interacted with STAT2, suggesting that aa 51-112 and 243-312 of USP18 are two important regions for the STAT2-USP18 interaction ( xref )."
reach
"Although the precise molecular mechanisms underlying the non-catalytic function of USP18 remain incompletely understood, data suggest that there is a direct interaction between USP18 and STAT2, which is crucial for recruiting USP18 to the plasma membrane, where it competes with janus kinase 1 (JAK1) for binding to IFNAR2."
reach
"3D modelling of the STAT2-USP18 heterodimer showed both the amino acid residues, A219 and R148, to localize to the interface between STAT2 and USP18 (Fig. 2c), suggesting that the A219, like the R148, residue might play an essential role in mediating a STAT2-USP18 protein interaction."
sparser
"Consistent with our suspicion that this might impair the STAT2:USP18 interaction through electrostatic or steric hindrance, co-immunoprecipitation experiments in U6A cells stably expressing WT or STAT2 R148W demonstrated a significant reduction of USP18 pull-down with STAT2 R148W compared to WT ( xref ), providing a molecular mechanism for the USP18 insensitivity of patient cells."
sparser
"It is also notable that those molecular defects that result in a failure of negative regulation of IFNAR signaling (i.e. STAT2 R148W and USP18 -/- ) lead to more serious and extensive systemic inflammatory disease than do defects of excessive IFNα/β production ( xref ), suggesting that the STAT2:USP18 axis acts to limit an immunopathogenic response towards both physiological ( xref ) and pathological ( xref ) levels of IFNα/β."
sparser
"The underlying mechanism involves unchecked USP18- and STAT2-dependent regulation of the type I IFN response pathway, as confirmed by the identification of patients homozygous for STAT2 variants disrupting the interaction of STAT2 with USP18 ( xref – xref ) and of patients with complete or partial AR USP18 deficiency ( xref – xref ), who also have a type I interferonopathy."
sparser
"Although the precise molecular mechanisms underlying the non-catalytic function of USP18 remain incompletely understood, data suggest that there is a direct interaction between USP18 and STAT2, which is crucial for recruiting USP18 to the plasma membrane, where it competes with janus kinase 1 (JAK1) for binding to IFNAR2."
sparser
"In this model, I60N is located near the USP18-STAT2 interface ( xref C and S7D), which is critical for scaffold function. xref , xref Due to species-specific differences in USP18-ISG15-STAT2 protein-protein interactions, the analogous mutation in mUSP18, I57, may not result in a similar scaffold impairment. xref Future genome-wide CRISPR screening strategies paired with endogenous IPs of WT, catalytic, and scaffold mutants may help identify effector pathways and protein-protein interactions mediating USP18-dependent IFN sensitivity across cancer types."