The Coronavirus Transmissible Gastroenteritis Virus Evades the Type I Interferon Response through IRE1α-Mediated Manipulation of the MicroRNA miR-30a-5p/SOCS1/3 Axis

Abstract

In host innate immunity, type I interferons (IFN-I) are major antiviral molecules, and coronaviruses have evolved diverse strategies to counter the IFN-I response during infection. Transmissible gastroenteritis virus (TGEV), a member of the family, induces endoplasmic reticulum (ER) stress and significant IFN-I production after infection. However, how TGEV evades the IFN-I antiviral response despite the marked induction of endogenous IFN-I has remained unclear. Inositol-requiring enzyme 1 α (IRE1α), a highly conserved ER stress sensor with both kinase and RNase activities, is involved in the IFN response. In this study, IRE1α facilitated TGEV replication via downmodulating the host microRNA (miR) miR-30a-5p abundance. miR-30a-5p normally enhances IFN-I antiviral activity by directly targeting the negative regulators of Janus family kinase (JAK)-signal transducer and activator of transcription (STAT), the suppressor of cytokine signaling protein 1 (SOCS1), and SOCS3. Furthermore, TGEV infection increased SOCS1 and SOCS3 expression, which dampened the IFN-I antiviral response and facilitated TGEV replication. Importantly, compared with mock infection, TGEV infection resulted in decreased miR-30a-5p levels and significantly elevated SOCS1 and SOCS3 expression in the piglet ileum. Taken together, our data reveal a new strategy used by TGEV to escape the IFN-I response by engaging the IRE1α-miR-30a-5p/SOCS1/3 axis, thus improving our understanding of how TGEV escapes host innate immune defenses. Type I interferons (IFN-I) play essential roles in restricting viral infections. Coronavirus infection induces ER stress and the interferon response, which reflects different adaptive cellular processes. An understanding of how coronavirus-elicited ER stress is actively involved in viral replication and manipulates the host IFN-I response has remained elusive. Here, TGEV inhibited host miR-30a-5p via the ER stress sensor IRE1α, which led to the increased expression of negative regulators of JAK-STAT signaling cascades, namely, SOCS1 and SOCS3. Increased SOCS1 or SOCS3 expression impaired the IFN-I antiviral response, promoting TGEV replication. These findings enhance our understanding of the strategies used by coronaviruses to antagonize IFN-I innate immunity via IRE1α-mediated manipulation of the miR-30a-5p/SOCS axis, highlighting the crucial role of IRE1α in innate antiviral resistance and the potential of IRE1α as a novel target against coronavirus infection.

Human Coronavirus: Host-Pathogen Interaction

“…Moreover, UPR transcription factors such as XBP1 may directly bind to the promoter/enhancer of IFN-β and IL-6 to activate transcription (78). Recently, it was found that while the PERK branch of UPR suppressed TGEV replication by activating NF-κB-dependent IFN-I production (131), the IRE1 branch indeed facilitated IFN-I evasion by downregulating the expression level of miRNA miR-30a-5p (75). Whether similar mechanisms apply during HCoV infection will require further investigation.…”

miR-26a Inhibits Feline Herpesvirus 1 Replication by Targeting SOCS5 and Promoting Type I Interferon Signaling

“…In this study, overexpression of SOCS5 can inhibit IFN-induced signalling and promote FHV-1 replication, while knockdown of endogenous SOCS5 enhances the IFN-I signalling cascade and suppresses FHV-1 replication (Figure 7), which further verified the negative regulatory role of SOCS5. Previous studies have reported that some miRNAs are involved in the innate immune response by targeting SOCS family proteins [22][23][24]. We found that miR-26a can directly target SOCS5 and decrease its expression and promote the STAT1 phosphorylation, which is used to inhibit viral replication by the host.…”

“…miR-155 feedback enhanced type I IFN signalling by suppressing SOCS1 and inhibiting viral replication [21]. miR-30a-5p downregulated the expression of SOCS1 and SOCS3 via directly targeting their 3' UTRs [22], which also enhanced IFN-I antiviral signalling. miR-130b and miR-432 enhanced the expression of IFN-β by targeting cellular SOCS5 [23,24].…”

Porcine Reproductive and Respiratory Syndrome Virus Enhances Self-Replication via AP-1–Dependent Induction of SOCS1

“…Okumura et al (38) demonstrated that Ebola virus-like particles stimulate the induction of SOCS3, leading to enhanced ubiquitinylation and budding of Ebola virions. Recent studies have shown that some viruses, like Japanese encephalitis virus and transmissible gastroenteritis virus, employ microRNAs to manipulate SOCS protein expression, thus evading cellular antiviral responses for promoting virus replication (41,42). Thus, it can be seen that viruses hijack the host SOCS system through different mechanisms to influence viral replication, pathogenesis, and immune evasion.…”