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The Hippo Pathway and Viral Infections

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Review

The Hippo Pathway and Viral Infections

Zhilong Wang et al. Front Microbiol.

Abstract

The Hippo signaling pathway is a novel tumor suppressor pathway, initially found in Drosophila. Recent studies have discovered that the Hippo signaling pathway plays a critical role in a wide range of biological processes, including organ size control, cell proliferation, cancer development, and virus-induced diseases. In this review, we summarize the current understanding of the biological feature and pathological role of the Hippo pathway, focusing particularly on current findings in the function of the Hippo pathway in virus infection and pathogenesis.

Keywords: Yes-associated protein; hippo; pathogenesis; signaling pathway; virus.

Figures

FIGURE 1
FIGURE 1
The core Hippo pathway in mammals. Tao kinases 1–3 phosphorylate and activate MST1/2. Interactions between MST1/2 and SAV1 induce LATS1/2 activity. Phosphorylation of MOB1 by MST1/2 enhances MOB1 interactions with LATS1/2, leading to full activation of LATS1/2. NF2 interacts with LATS1/2 and facilitates LATS1/2 phosphorylation by the MST1/2-SAV1 complex. Members of the MAP4K family are identified as direct LATS1/2 activated kinases. cyclic adenosine monophosphate (cAMP) can also activate LATS1/2 kinases via protein kinase A (PKA) and Rho GTPases, whereas LPA (lysophosphatidic acid) and S1P (sphingosine 1- phosphophate) are shown to inhibit the activity of LATS1/2 kinases via G protein coupled receptor (GPCR). Phosphorylation of YAP on Ser127 (TAZ on Ser89)induces binding of YAP (TAZ) with 14-3-3, and induces cytoplasmic retention of YAP (TAZ). Phosphorylation of YAP on Ser381 (TAZ on Ser311) triggers subsequent phosphorylation by casein kinase 1 (CK1δ/ε), resulting in the recruitment of SCFβ-TRCP E3 ligase and ubiquitination, and the proteasomal degradation of YAP. TEADs are the major transcriptional activator of YAP in mammals, and YAP binding to TEADs is required for inducing target gene expression. Smad, RUNX1/2, p63/p73, and ErbB4 may be transcriptional factors of YAP/TAZ. YAP and TEADs mediate the expression of target genes such as CTGF, CYR61, Birc5, FGF1, RASSF1A, and others.
FIGURE 2
FIGURE 2
Domain organization and key modifications of YAP/TAZ proteins. YAP is a proline-rich phosphoprotein mainly consisting of the SH3 binding domain, two WW domains and a highly conserved PDZ binding motif FLTWL at the C-terminus. TAZ is homologous to YAP and has only one WW domain. YAP/TAZ is phosphorylated by LATS1/2 on Ser61, Ser109, Ser127, Ser164, and Ser381 (TAZ Ser66, Ser89, Ser117, and Ser311) in the HxRxxS motifs.
FIGURE 3
FIGURE 3
Hippo pathway plays vital role in mammalian immune system. The Hippo core component MST1/2 and YAP can inhibit innate immunity caused by viral infection through the RIG-I/cGAS-TBK1/IKKε-IRF3 axis. IKKε promotes the degradation of YAP to activate cellular antiviral responses. Hippo pathway is also involved in adaptive immunity. MST1/2 enhances T cell migration by activating LFA-1 though DENND1C-RAB13 and VASP signaling, or via MST1-MOB1-Dock8-Rac1 axis. MST1/2 promotes regulatory T cell (Treg) differentiation by modulating the Foxp3 expression. YAP promotes the expression of Foxp3, whereas TAZ inhibits its function. Moreover, MST1/2 and/or NDR1/2 may inhibit the development of T cells.
FIGURE 4
FIGURE 4
Hippo pathway is involved in viral infection. Abnormal regulation of the Hippo pathway has been observed during infection with a variety of viruses such as HBV, HCV, MCV, ZIKV, EBV, KSHV, HPV, and MuPyV. Viruses exert their carcinogenic function by regulating the expression, degradation, and nuclear retention of YAP/TAZ proteins.

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References

    1. Abdollahpour H., Appaswamy G., Kotlarz D., Diestelhorst J., Beier R., Schaffer A. A., et al. (2012). The phenotype of human STK4 deficiency. Blood 119 3450–3457. 10.1182/blood-2011-09-378158 - DOI - PMC - PubMed
    1. Alzahrani F., Clattenburg L., Muruganandan S., Bullock M., Macisaac K., Wigerius M., et al. (2017). The Hippo component YAP localizes in the nucleus of human papilloma virus positive oropharyngeal squamous cell carcinoma. J. Otolaryngol. Head Neck Surg. 46 15. 10.1186/s40463-017-0187-1 - DOI - PMC - PubMed
    1. Biswas S., Smith G. L., Roy E. J., Ward B., Shisler J. L. (2018). A comparison of the effect of molluscum contagiosum virus MC159 and MC160 proteins on vaccinia virus virulence in intranasal and intradermal infection routes. J. Gen. Virol. 99 246–252. 10.1099/jgv.0.001006 - DOI - PMC - PubMed
    1. Boggiano J. C., Vanderzalm P. J., Fehon R. G. (2011). Tao-1 phosphorylates Hippo/MST kinases to regulate the Hippo-Salvador-Warts tumor suppressor pathway. Dev. Cell 21 888–895. 10.1016/j.devcel.2011.08.028 - DOI - PMC - PubMed
    1. Cancer Genome Atlas Research Network (2014). Comprehensive molecular characterization of gastric adenocarcinoma. Nature 513 202–209. 10.1038/nature13480 - DOI - PMC - PubMed

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