Fig 1.
Viral modulation of Hippo-YAP signalling and its crosstalk with innate antiviral immunity.
Schematic illustrating how viral infections regulate the Hippo pathway and its interaction with cytosolic antiviral sensing pathways to influence interferon responses. Hepatitis B virus (HBV) activates Toll-like receptor 2 (TLR2), signalling through MyD88 and IRAK4 to modulate PP2A and the core Hippo kinase MST1/2. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) activates MST1/2 and LATS1/2, while HIV also influences LATS1/2 activity and promotes crosstalk with the PQBP1-cGAS axis. Coxsackievirus B (CVB) increases YAP expression at the mRNA level. Zika virus is shown as an example of infection-associated metabolic stress, in which ATP depletion and increased AMP levels activate AMPK, linking cellular energy status to Hippo-YAP regulation and innate immune signalling. Activation of MST1/2 and LATS1/2 leads to phosphorylation of YAP/TAZ, promoting their cytoplasmic retention and regulating their transcriptional activity. When active, YAP/TAZ translocate to the nucleus and associate with TEAD transcription factors to regulate target gene expression. In parallel, viral nucleic acids are detected by cytosolic sensors including PQBP1, cGAS, and RIG-I, which signal through STING or MAVS to activate TBK1 and IKKε. These kinases phosphorylate IRF3, leading to its dimerisation, nuclear translocation, and induction of immune response genes, including interferon-β (IFNβ) and downstream interferon-stimulated genes (ISGs). Crosstalk between Hippo signalling and innate immune pathways influences the magnitude and outcome of antiviral responses. YAP/TAZ can suppress TBK1-mediated IRF3 activation, illustrating reciprocal crosstalk between Hippo signalling and innate antiviral immunity. Created in BioRender. Ardestani, A. (2026) https://BioRender.com/0dmjgn6.
Fig 2.
Viral manipulation of Hippo-YAP/TAZ signalling to regulate viral replication and host transcriptional responses.
Schematic showing how different viruses interact with the Hippo pathway to control YAP/TAZ activity and downstream transcription. Activation of the core Hippo kinases MST1/2 and LATS1/2 and their partners SAV1 and MOB1 leads to phosphorylation of YAP/TAZ, regulating their subcellular localisation and transcriptional function. During Ebola virus infection, LATS1/2 is recruited to viral inclusion bodies, where it phosphorylates the viral protein VP30. Phosphorylated VP30 participates in the viral transcriptional complex containing NP, VP35, and the viral polymerase L, thereby regulating primary viral transcription. During SARS-CoV-2 infection, YAP/TAZ translocate to the nucleus and interact with TEAD transcription factors to regulate host gene expression. However, the viral protein helicase NSP13 promotes recruitment of transcriptional repressors to the YAP/TAZ-TEAD4 complex, suppressing target gene transcription. TEAD4 may function as a scaffold to recruit both NSP13 and YAP, and NSP13 likely inactivates the YAP/TEAD4 transcriptional complex by inducing chromatin remodelling and recruiting repressive proteins to the YAP/TEAD/NSP13 complex. During influenza A virus infection, the viral non-structural protein NS1 physically interacts with the C-terminal domain of YAP/TAZ within the YAP/TAZ–TEAD complex, enabling recruitment of histone deacetylases HDAC4/6 to the TLR3 promoter. YAP binds a putative TEAD-binding motif at this locus, and HDAC4/6-mediated reduction of histone H3 acetylation leads to chromatin remodelling and transcriptional silencing of TLR3, thereby suppressing antiviral innate immune signalling. In the absence of this repression, YAP/TAZ-TEAD promote TLR3 transcription. These examples illustrate that viruses can manipulate Hippo-YAP signalling at multiple levels, including upstream kinase activity, viral protein phosphorylation, and YAP/TEAD-dependent host transcription. Created in BioRender. Ardestani, A. (2026) https://BioRender.com/ihv7etr.