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Review
. 2024 Oct 16;15(10):e0258224.
doi: 10.1128/mbio.02582-24. Epub 2024 Sep 20.

Interference without interferon: interferon-independent induction of interferon-stimulated genes and its role in cellular innate immunity

Shachee Swaraj  1   2 , Shashank Tripathi  1   2
Affiliations
Review

Interference without interferon: interferon-independent induction of interferon-stimulated genes and its role in cellular innate immunity

Shachee Swaraj et al. mBio. .

Abstract

Interferons (IFNs) are multifaceted proteins that play pivotal roles in orchestrating robust antiviral immune responses and modulating the intricate landscape of host immunity. The major signaling pathway activated by IFNs is the JAK/STAT (Janus kinase/signal transducer and activator of transcription) pathway, which leads to the transcription of a battery of genes, collectively known as IFN-stimulated genes (ISGs). While the well-established role of IFNs in coordinating the innate immune response against viral infections is widely acknowledged, recent years have provided a more distinct comprehension of the functional significance attributed to non-canonical, IFN-independent induction of ISGs. In this review, we summarize the non-conventional signaling pathways of ISG induction. These alternative pathways offer new avenues for developing antiviral strategies or immunomodulation in various diseases.

Keywords: ISG induction; JAK kinases; STAT signaling; innate immunity; interferon-independent immunity; interferons; viral immunity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig 1
Fig 1
Schematic representation of various non-canonical ISG induction mechanisms. This figure outlines the alternative stimuli that can trigger ISG transcription, bypassing the canonical IFN-JAK-STAT axis.
Fig 2
Fig 2
Canonical and non-canonical ISG induction pathways. Viruses are recognized by PRRs like RIG-I/MDA5, cGAS, or TLRs that activate TFs, including IRFs, NF-κB, and so on, via adaptor proteins including MAVS, MyD88, or STING. These TFs trigger IFNs and proinflammatory cytokines, leading to ISG induction via the JAK/STAT cascade. Unconventionally, these TFs can drive transcription of a subset of ISGs by directly binding to their ISREs upon immune stimulation. IL-27, pex-MAVS, U-ISGF3, RA, TNF-α, and NSI, like Brequinar, also drive ISG transcription via unique pathways. Solid black arrows: canonical signaling; dashed red arrows: non-canonical signaling. ER: endoplasmic reticulum.
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