Preprint Inflammatory Cytokines Can Induce Synthesis Of Type-I Interferon, 2024, Sharma et al.

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Inflammatory Cytokines Can Induce Synthesis Of Type-I Interferon
Nikhil Sharma; Xu Qi; Patricia Kessler; Ganes C. Sen

Type I interferon (IFN) is induced in virus infected cells, secreted and it inhibits viral replication in neighboring cells. IFN is also an important player in many non-viral diseases and in the development of normal immune cells. Although the signaling pathways for IFN induction by viral RNA or DNA have been extensively studied, its mode of induction in uninfected cells remains obscure.

Here, we report that inflammatory cytokines, such as TNF-α and IL-1β, can induce IFN-β through activation of the cytoplasmic RIG-I signaling pathway. However, RIG-I is activated not by RNA, but by PACT, the protein activator of PKR. In cell lines or primary cells expressing RIG-I and PACT, activation of the MAPK, p38, by cytokine signaling, leads to phosphorylation of PACT, which binds to primed RIG-I and activates its signaling pathway.

Thus, a new mode of type I IFN induction by ubiquitous inflammatory cytokines has been revealed.

Key points.

• Cytochalasin D followed by TNF-α / IL-1β treatment activates IFN-β expression.

• IFN-β expression happens due to activation of RIG-I signaling.

• Interaction between RIG-I and PACT activates IFN-β expression.

Link | PDF (Preprint: BioRxiv)

 

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The signaling pathways used by viruses to induce IFN have been extensively studied; they are triggered primarily by recognition of intracellular viral nucleic acids by endosomal or cytoplasmic pattern recognition receptors such as TLRs, cGAS/STING or RLRs. However, IFNs are involved in many physiological and pathological processes, above and beyond viral infection. For example, B cell maturation and T cell functions require the participation of IFNs and type I IFNs play both positive and negative roles in a variety of cancers and autoimmune diseases. It is unclear how IFN is induced in the absence of virus infection, although cellular nucleic acids may participate in the process.

Viral double-stranded (ds) RNA triggers several antiviral responses in an infected cell. It can activate RIG-I signaling to induce IFN, which, in turn, induces antiviral genes. The dsRNA can also activate two antiviral enzymes 2-5 OAS and PKR. The dsRNA binding to PKR causes its activation by auto-phosphorylation and active PKR can inhibit protein synthesis by phosphorylating the translation initiation factor eIF-2α.

An alternative activator of PKR is PACT, another dsRNA-binding protein, which can activate PKR without any involvement of dsRNA. [...] two serine residues in the latter domain, S246 and S287, need to be phosphorylated for its ability to activate PKR in cells. S246 is constitutively phosphorylated but S287 is phosphorylated in response to various extracellular stresses.

Here we report that inflammatory cytokines, such as TNF-α or IL-1β, can induce IFN-β by activating PACT, which binds to RIG-I and trigger its signaling in the absence of any viral RNA. However, RIG-I needs to be primed for PACT activation. Acharya et al reported that viral activation of RIG-I is a two-step process; first RIG-I is dephosphorylated by a phosphatase and then the primed RIG-I is activated by viral dsRNA. The current study shows that PACT, activated by the MAP kinase, p38, can substitute for dsRNA to activate signaling by primed RIG-I and thereby provides a means to IFN production by uninfected cells exposed to inflammatory cytokines.

 

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RLR — See RIG-I-like receptors: their regulation and roles in RNA sensing (2020, Nature Reviews Immunology)