Figure 3.

Canonical ISG15 functions in key cellular processes. (1) Inhibition of viral proteins. ISG15 modifies numerous viral proteins and is capable of disrupting their oligomerisation, function and interaction with host pathways. (2) Extracellular cytokine activity. Free ISG15 can be secreted as a cytokine and stimulate IFNγ release through interaction with the LFA-1 receptor. (3) Regulation of IFN signalling. The ISG15-protease USP18 interferes with type-I IFN signalling via direct interaction with the INFAR2 subunit of the IFN receptor. This displaces JAK1 and prevents JAK/STAT signal transduction. Non-conjugated ISG15 binds and stabilises USP18. (4) Inhibition of proteasomal degradation. ISGylation can interfere with ubiquitin-mediated proteasomal degradation through inhibition of E3 ligases, competition for lysine conjugation sites and formation of mixed chains. Alternatively, ISG15 can promote proteasomal degradation through stimulation of CHIP (aka STUB1) activity. (5) Selective autophagy. ISG15 can promote selective autophagy of target proteins. In the case of RIG-1, ISG15 association allows for interaction with LRCC25, facilitating p62-guided RIG-1 degradation via the autophagosome. Conversely, ISGylation of the autophagy-promoting protein BECN1 prevents its activity through disrupting its ubiquitin-mediated interaction with PIK3C3. (6) Inhibition of protein translation. ISGylation of PKR promotes phosphorylation and activation of the translational suppressor elF2α. Similarly, ISGylation of 4EHP increases its affinity to 7-methylguanosine mRNA cap binding, displacing elF4F and inhibiting protein translation. Figure created using BioRender.com (2020).