While the dogma of the mainstream considers

While the dogma of the mainstream considers Hippo pathway as a series of size-controlling kinases, there were still some controversial data supporting that YAP, a vital oncoprotein of Hippo downstream, is antagonistic to regenerative proliferation [[20], [21], [22]]. Known for its expansion-driving ability, YAP counterbalances the growth-promoting effect of Wnt/β-Catenin pathway in regenerative intestines [20]. More intriguingly, YAP facilitates DNA damage-induced apoptosis by interacting with p73, a homolog of p53 [23], in hematological malignancies [21,24]. Besides YAP, the upstream members LATS1 and LATS2 also behave oppositely [22]. They are supposed to phosphorylate YAP, helping to accomplish its cytoplasmic sequestration and restrict cellular proliferation; yet their inactivation triggers immune responses, which in turn destroy the very Koumine with LATS1/2 silenced, keeping homeostasis of an immune-competent individual. Controversial roles of Hippo might exist in different contexts [25], but how it functions discrepantly remains largely vague.
The paradox of YAP phosphorylation Notably, there was a recent study that mentioned two completely opposite functions of Hippo: growth promotion or inhibition [22]. In fact, the core process of Hippo activation is attributed to YAP phosphorylation. Thus, the kernel of this issue might be translated into: whether the phosphorylated YAP keeps activation or goes to an invalidation. Besides Hippo, which has been well illustrated to phosphorylate YAP on S127 to achieve YAP cytoplasmic retention [13], there are still a number of other mechanisms regulating YAP: its S381 phosphorylation leads to degradation [26]; its Y357 phosphorylation activates cell apoptosis [27]. Yet, its phosphorylation by YES1 triggers anti-apoptotic effects [28]. The scenarios may vary from cellular contexts and signaling crosstalks, and the details of this debatable theme have been summarized elsewhere [29]. Along with this line, this dual character of Hippo is applicable in regards its immune capability. Similar to the antimicrobial role of Hippo in Drosophila, YAP was recently identified to be involved in anti-virus process, even though Hippo is taken over [30,31]. Outside the frame of Hippo, YAP was proved to inversely mediate interferon (IFN)-β signaling pathway [32]. Normally, after the viral invasion, exogenous nucleic acids stimulate IκB kinase (IKK)-associated pathways, causing secretion of IFN-α and IFN-β, as well as proinflammatory cytokines, and waking protective responses [33,34]. In this setting, the existence of YAP counteracts the antiviral signaling IFN-β by secluding IRF3, the most downstream effector of this signaling, in the cytoplasm [32]. Nevertheless, after viral infection, IKKɛ phosphorylates YAP on Ser403, which makes YAP targeted by lysosome and sent to degradation. This IKKɛ-dependent deterioration of phosphorylated YAP ensures an anti-virus immunity of an individual.
The anti-inflammatory role of Hippo-YAP axis From flies to vertebrates, illustrated by various scientists, there is an emerging theme that Hippo becomes a part of the immune response [30,31,35,36]. Recently, a group of researchers has demonstrated that, for adult flies, Hippo plays an important role in anti-pathogen immunity [30]. Unpaired 3 (Upd3) is a member of IL-6 family cytokines in Drosophila, whose secretion is regulated by Scalloped (Sd, a member of TEAD family). Silence of Hippo after enteric infections impaired Upd3 expression, which suppressed the growth of intestinal stem cell and led those adult flies to worse outcomes. Similarly, Bo Liu et al. pointed out that Gram-positive bacteria give rise to an acute activation of Hippo cascade, which restricts a strong antimicrobial reaction [31]. Owing to the fact that this acute infection stimulates Toll pathway, which dampened Hippo's inhibitor, therefore when facing S. aureus infection, Yki shifted rapidly from the nucleus to cytoplasm within half an hour, and it displayed a divergent distribution all over the cell instead of an accumulation in the nucleus afterward. Given that, through both in vitro and in vivo studies, the Yki-Sd complex was found to directly activate the expression of Cactus (Cact), an essential protein in innate immunity which has been previously reported to be degraded through Toll signaling [37]. Accordingly, along with the abundance of Cact, more antimicrobial peptides (AMPs) are released through a mechanism of humoral immunity within a fly [38]. Besides, an overabundance of AMPs brings neurotoxic effects to this creature and elicits neurodegeneration via overacting immune responses [35,39]. In order to limit the vulnerability, this infection-induced Hippo activation realizes Yki cytoplasmic sequestration, which subsequently reduces Cact expression and decreases the release of antimicrobial peptides [32]. Aiming at this Yki/Sd-Cact axis likewise, one of the latest projects, has suggested that Yki is capable of impeding this neurodegeneration [35]. Other than organ size controlling, the findings above shed light on the role of Hippo in a different way (Fig. 1).