C57BL/6JCya-Oas2^em1flox/Cya

Oas2, a member of the 2'-5'-oligoadenylate synthetases (OAS) family, is an interferon (IFN)-induced antiviral enzyme [1,2,3,4,6,7,8,9]. It generates 2'-5'-linked oligoadenylates upon activation by double-stranded RNA, which can activate ribonuclease L to degrade single-stranded RNA. This process is involved in the antiviral response system and can also influence the IFN-activated Jak/STAT signaling pathway [3,7].

In breast cancer, high mRNA expression of Oas2 is associated with favorable prognosis, while in psoriasis, its overexpression is found in lesional skin and serum, and it contributes to epidermal keratinocyte proliferation by regulating the cell cycle and augmenting IFN-1-induced phosphorylation of Jak1 and signal transducer and activator of transcription 1 [1,2]. Inborn errors of Oas2 in children are related to SARS-CoV-2-related multisystem inflammatory syndrome (MIS-C), where Oas2-deficient monocytic cell lines produce excessive inflammatory cytokines upon dsRNA or SARS-CoV-2 stimulation [3]. Activation of Oas2 in a mouse model with an activating mutation prevented pregnancy-driven mammary cancer metastases and enhanced the effectiveness of checkpoint immunotherapy [4]. In testicular cancer, upregulating Oas2 by piR-36249 and DHX36 inhibits cancer cell progression [5]. Oas2 also restricts intracellular Mycobacterium tuberculosis replication, enhances pro-inflammatory cytokine secretion, and inhibits Zika virus replication through activation of the type Ι IFN signaling pathway [6,7]. In COVID-19, genetic variants in the gene cluster encoding Oas2 are associated with critical illness [8]. The activity of Oas2 is affected by the characteristics of double-stranded RNA, with a minimum dsRNA length requirement of 35 bp for activation [9]. In psoriasis, Oas2 is a potential biomarker for disease activity [10].

In conclusion, Oas2 plays crucial roles in multiple biological processes and disease conditions. Its functions range from antiviral responses to influencing cell proliferation, metastasis, and inflammation in various diseases such as cancer, psoriasis, and COVID-19. Studies using genetic models, especially in mice, have provided valuable insights into these functions, helping to understand the underlying mechanisms and potentially guiding the development of therapeutic strategies.