An alternatively transcribed TAZ variant negatively regulates JAK ‐ STAT signaling

Abstract

Type I interferon (IFN)‐induced Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling drives the expression of IFN‐stimulated genes (ISGs) to mediate antiviral response. The strength and duration of JAK‐STAT signaling are tightly regulated to ensure effective antiviral defense while avoiding pathological inflammation and autoimmunity. Here, we report that cTAZ, an isoform of the Hippo pathway effector TAZ, is transcribed by an alternative promoter. Although majority of C‐terminal sequences of TAZ is retained, cTAZ is not regulated by the Hippo signaling and does not mediate its growth‐inhibitory functions. Instead, cTAZ negatively regulates JAK‐STAT signaling by inhibiting STAT1/2 nuclear localization and ISG expression, and its expression is induced by type I IFN. Thus, cTAZ functions as a modulator of JAK‐STAT signaling and may play a role in fine‐tuning cellular antiviral response.

cTAZ : a safeguard factor of antiviral response

“…TAZ half‐life is prolonged in LATS1/2 −/− cells, while that of cTAZ is unaffected. Furthermore, the expression of two bona fide transcriptional targets of TEAD, CTGF and CYR61, is not modulated by ectopic expression of cTAZ . Collectively, these findings clearly show that cTAZ, unlike TAZ, is not a canonical Hippo transducer.…”

“…Notably, Fang et al provide evidence that gVSV infection promotes cTAZ expression and that cTAZ is a target of JAK-STAT signalling [1]. STAT1 is recruited to the cTAZ promoter, which contains specific STAT1 binding sites, and upon IFN-c stimulation modulates transcriptionally cTAZ expression (Fig 1 lower panel) [1]. Thus, cTAZ could be a critical component of negative regulatory feedbacks controlling JAK-STAT signalling during antiviral response.…”

“…This implies that the strict regulation of this signalling pathway is essential to prevent pathological consequences. In this issue of EMBO Reports, Fang et al [1] describe an alternative variant of TAZ, called cTAZ, which fine-tunes JAK-STAT signalling, thereby contributing to the tight control of antiviral responses. T AZ (transcriptional co-activator with PDZ-binding motif) is the mammalian transcriptional co-activator homologue of YAP [2].…”

The Hippo Pathway in Innate Anti-microbial Immunity and Anti-tumor Immunity

“…Other groups also revealed that YAP/TAZ attenuated NF-κB signaling by directly inhibiting IKKα/β activation in an osteoarthritis murine model (88) and by associating with TRAF6 and facilitating TRAF6 degradation in vascular inflammation (90). Recently, the Yu group reported that an isoform of TAZ impeded JAK-STAT signaling to dampen the type I IFNs pathway (86). In addition, our group found that, independent of LATS kinases and YAP/TAZ, MST1 directly associated with and phosphorylated IRF3 to attenuate its dimerization and promoter binding (109), and our and other groups further revealed that MST1 was also suppressive of TBK1 activation (109,110).…”

“…The Hippo pathway appears considerably involved in the regulation of innate immunity during pathogen infection, which is largely distinct from its canonical roles in organ growth control and tissue homeostasis maintenance. Our group and others have revealed that YAP and TAZ functioned as potent suppressors to compromise the production and signaling of type I interferons (IFN-Is) (41,85,86) and the activation of NF-κB (42) and that they served as positive regulators for differentiation of the Treg lymphocytes (87). For example, Zhang et al revealed that YAP and TAZ acted as potent suppressors of TBK1, the central kinase in innate nucleic acid-sensing signaling (33); Deng et al revealed that YAP/TAZ attenuated NF-κB signaling by directly inhibiting IKKα/β activation in an osteoarthritis murine model (88); Ni et al found that YAP was highly expressed in Treg cells to amplify TGFβ-SMAD activation, which strengthened Foxp3 expression and Treg functions (87).…”