Insulin receptor substrate-4 interacts with ubiquitin-specific protease 18 to activate the Jak/STAT signaling pathway

Abstract

Ubiquitin-specific protease 18 (USP18) as a negative regulator of the Jak/STAT signaling pathway plays an important role in the host innate immune response. USP18 has been shown to bind to the type I interferon receptor subunit 2 (IFNAR2) to down-regulate the Jak/STAT signaling. In this study, we showed that insulin receptor substrate (IRS)-4 functioned as a novel USP18-binding protein. Co-precipitation assays revealed that two regions (amino acids 335–400 and 1094-1257) of IRS4 were related to bind to the C- terminal region of USP18. IRS4 binding to USP18 diminished the inhibitory effect of USP18 on Jak/STAT signaling. IRS4 over-expression enhanced while IRS4 knock-down suppressed the Jak/STAT signaling in the presence of IFN-a stimulation. As such, IRS4 increased IFN-a-mediated anti-HCV activity. Mechanistically, IRS4 promoted the IFN-a-induced Jak/STAT signaling by interact with USP18. These results suggested that IRS4 binds to USP18 to diminish the blunting effect of USP18 on IFN-a-induced Jak/STAT signaling. Our findings indicated that IRS4 is a novel USP18-binding protein that can be used to boost the host innate immunity to control HCV, and potentially other viruses that are sensitive to IFN-a.

Analysis of the early response to spinal cord injury identified a key role for mTORC1 signaling in the activation of neural stem progenitor cells

“…3 and Supplementary Table S4 ). Among the genes included in these GO terms, we found irs4, which inhibits JAK/Stat signaling pathway, modulating the immune response 32 ; PDE5A (phosphodiesterase 5A), whose pharmacological inhibition have been associated with anti-inflammatory and neuroprotective effects 33 ; and shh (sonic hedgehog), which has been implicated in macrophage polarization after SCI, regulating pro- and anti-inflammatory response 34 . This analysis suggests that there is an active mechanism to control and limit the immune response.…”

USP18 is a significant driver of memory CD4 T-cell reduced viability caused by type I IFN signaling during primary HIV-1 infection

“…Of note, the IFN-I regulatory functions of USP18 depend on its capacity to bind IFNAR2 and inhibit JAK/STAT signaling and involves other factors. Through direct interaction with USP18, the insulin receptor substrate-4 was shown to counteract its inhibitory effect on JAK/STAT signaling [51]. Conversely, STAT2 was shown to be a crucial component of the USP18-mediated suppression of IFN-I signaling [52].…”

The development of COVID-19 treatment

“…When ligands bind to their receptors, the intracellular portion of JAKs will be activated, which recruits and phosphorylates STATs. Activated STATs translocate into the nucleus and bind to the promoters of related genes, inducing the expression of specific genes (120)(121)(122)(123). These cytokines are highly important in initiating and orchestrating innate and adaptive immune responses but may also be a source of excessive or uncontrolled inflammation and tissue damage in patients with COVID-19.…”