Schematic representation of IFN-α receptor signaling. IFN-α receptor (IFNΑR) is composed of the IFNAR1 and IFNAR2 subunits and lacks intrinsic kinase activity, which is compensated by a constitutive association with the Janus tyrosine kinases (Jak) in their cytosolic portion: Tyk2 with IFNAR 1 and Jak1 with IFNAR2. The binding of IFN-α induces a major conformational change of IFNAR that brings Jak1 and Tyk2 in close contact, allowing cross-phosphorylation of the Jaks as the first activating event. The canonical type I IFN signaling pathway relies on the phosphorylation (P) and nuclear translocation of signal transducers and activators of transcription (STAT) proteins, STAT1 and STAT2, that can form homo- or heterodimers. Activated STAT dimers can translocate in the nucleus and ultimately bind to specific sequences within the promoters of IFN-stimulated genes (ISG), leading to their transcription. Alternative pathways have also been identified, involving MAP-kinases and phosphoinositide 3 (PI3)-kinases/mammalian target of rapamycin (mTOR) pathways. In addition, IFNAR activation can lead to increased number and size of nuclear bodies composed of the promyelocytic leukemia protein (PML). Such enhanced formation of nuclear bodies may drive PML-dependent senescence, a mechanism that can be involved in the elimination of malignant stem cells.⁴¹ Negative regulatory molecules that block IFN type I signaling (represented in red) include the ubiquitin-specific peptidase (USP) USP18 and SOCS1 (suppressor of cytokine signaling 1), among others. USP18 binds to IFNAR2 and inhibits the phosphorylation of Jak1 by blocking its interaction with IFNAR2. SOCS1 can directly inhibit Jak1and Tyk2 activity.