Type I interferons and endoplasmic reticulum stress in health and disease

Abstract

Type I interferons (IFNs) comprise of pro-inflammatory cytokines created, as well as sensed, by all nucleated cells with the main objective of blocking pathogens-driven infections. Owing to this broad range of influence, type I IFNs also exhibit critical functions in many sterile inflammatory diseases and immunopathologies, especially those associated with endoplasmic reticulum (ER) stress-driven signaling pathways. Indeed, over the years accumulating evidence has indicated that the presence of ER stress can influence the production, or sensing of, type I IFNs induced by perturbations like pattern recognition receptor (PRR) agonists, infections (bacterial, viral or parasitic) or autoimmunity. In this article we discuss the link between type I IFNs and ER stress in various diseased contexts. We describe how ER stress regulates type I IFNs production or sensing, or how type I IFNs may induce ER stress, in various circumstances like microbial infections, autoimmunity, diabetes, cancer and other ER stress-related contexts.

Keywords: Chemokine; Danger signals; IRE1; Inflammation; Interferon-stimulated genes (ISGs); NF-κB; Oncolytic viruses; PERK; STING; Toll-like receptors (TLRs); Unfolded protein response (UPR).

Fig. 1

A schematic depiction of production and sensing mechanisms for type I interferons (IFNs). Danger signals like lipopolysaccharide (LPS) or different nucleic acid species (single-stranded RNA or ssRNA, double-stranded RNA or dsRNA, CpG DNA) bind their cognate receptors like, Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5), or cyclic GMP-AMP (cGAMP) synthase (cGAS). These receptors execute a complex intracellular pathway that ultimately leads to the activation of transcription factors like IFN regulatory factor (IRF)-3/7 that eventually transcribe IFNα/β, which are thereafter translated and secreted. Upon extracellular emergence, IFNα/β bind to the IFNα receptor (IFNAR) complex, which causes activation of tyrosine kinase 2 (TYK2) and receptor-associated janus kinase 1 (JAK1). This eventually activates various downstream pathways that primarily aim to induce production of various interferon-stimulated genes (ISGs) derived protein products but also modulate cellular homeostasis. Of note, the inflammatory potential of IFNα/β is often limited by ubiquitination (Ub)-driven, lysosomal degradation of the IFNAR complex. AKT, protein kinase B alpha; ER, endoplasmic reticulum; IKKβ, I-kappa-B kinase beta; IKKɛ, I-kappa-B kinase epsilon; IRS1/2, insulin receptor substrate 1; ISRE, interferon-stimulated response element; MAVS, mitochondrial antiviral signaling protein; mTOR, mechanistic target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI-3K, phosphoinositide-3-kinase; STAT1/2/3/4/5/6, signal transducer and activator of transcription 1/2/2/4/5/6; STING, stimulator of interferon genes; TBK1, TANK-binding kinase 1.

Fig. 2

A broad depiction of the endoplasmic reticulum (ER) stress-driven unfolded protein response (UPR) signaling. See the text for further details on this pathway. S1P or S2P, site-1 or site-2 protease; eIF2α, eukaryotic translation initiation factor 2 alpha; PERK, protein kinase RNA-like ER kinase; ERAD, ER-associated protein degradation; CHOP, C/EBP homologous protein; XBP1, X-box binding protein 1; IRE1, inositol requiring enzyme 1; AP1, activator protein 1; TRAF2, TNF receptor-associated factor 2; ASK1, apoptosis signal-regulating kinase 1; JNK, c-Jun N-terminal kinase; BIM, BCL2-like protein 11; ATF4/6, activating transcription factor 4/6.