Geranylgeranylation promotes association of the OAS1 p46 isoform with intracellular membranes, in contrast to non-prenylated p42 isoform that remains primarily cytosolic (Kjær KH et al., 2014; Skrivergaard S et al., 2019; Soveg FW et al., 2021; Wickenhagen et al, 2021). During infection, particularly with positive-sense RNA viruses, such as flaviviruses, e.g., West Nile virus, Dengue virus, Zika virus, and coronaviruses such as SARS-CoV-2, which replicate in endoplasmic reticulum (ER)-derived membrane compartments, viral RNA is physically shielded from the cytosolic sensors. Prenylation of OAS1 p46 enhances its ability to detect membrane-protected viral double-stranded RNA (dsRNA) intermediates in the viral replication sites (Soveg FW et al., 2021; Wickenhagen et al, 2021). dsRNA-bound OAS1 synthesizes 2′-5′-linked oligoadenylates, which activate RNase L, leading to rapid translation arrest and subsequent RNA degradation, inhibiting viral replication (Donovan J et al., 2013; 2017).

Following prenylation, CAAX-containing proteins undergo proteolytic cleavage of the terminal AAX tripeptide. This reaction is catalyzed by endopeptidases such as RAS-converting enzyme 1 (RCE1), resulting in exposure of the prenylated cysteine as the new C-terminus. The exposed cysteine can then be methylated by isoprenylcysteine carboxyl methyltransferase (ICMT) (reviewed by Wang M & Casey PJ 2016; Cansado J 2018). This sequence of post-translational modifications is considered a common mechanism by which CAAX-containing proteins, including OAS1, are activated. However, there is no direct evidence for proteolytic removal of the C-terminal tripeptide or ICMT-mediated methylation of the C-terminal cysteine in OAS1; therefore, these steps are not depicted here.