# Dose-dependent activation of the Hippo pathway by Type I and Type III interferons suppresses tissue repair by human bronchial epithelial cells

## TL;DR

This study shows how high levels of interferons can slow tissue repair in the lungs by activating a specific pathway, separate from their antiviral effects.

## Contribution

The paper reveals a novel mechanism by which interferons suppress tissue repair via LATS1 activation, independent of STAT1.

## Key findings

- Type I and III interferons reduce bronchial cell migration and proliferation through LATS1 activation.
- LATS1 phosphorylation occurs via JAK activity, bypassing MST1/2 in the Hippo pathway.
- Higher IFN concentrations are needed to activate LATS1 compared to STAT1.

## Abstract

Interferons (IFNs) are potent antiviral cytokines that are rapidly activated when infected cells sense a virus, but continued IFN production following acute infection is linked to impaired recovery. IFNs protect against infection by inducing a suite of antiviral effectors in IFN receptor-expressing cells via JAK/STAT signaling. However, how IFNs curtail tissue repair is not fully understood. Here, we studied the effects of Type III IFNs (IFNλ1 and IFNλ2) and Type I IFN (IFNβ) on tissue repair functions of human bronchial epithelial cells (HBEC). We show that both Type III IFNs and IFNβ reduce bronchial epithelial cell migration and proliferation through a common upstream mechanism: activation of LATS1, a kinase best known for limiting organ growth as part of the Hippo signaling pathway. Mechanistically, Type III IFN or IFNβ curtailed wound healing by triggering phosphorylation of LATS1 via JAK activity, bypassing activation of MST1/2, the canonical activator of LATS1 in the Hippo pathway. Further experiments showed that distinct signaling pathways lead to LATS1 and STAT1 phosphorylation downstream of IFN receptor signaling. STAT1 was dispensable for IFN-mediated LATS1 phosphorylation and suppression of tissue repair, although as expected STAT1 was required for IFN-mediated protection from rhinovirus or influenza infection. Dose–response curve experiments revealed that higher concentrations of IFN were required to trigger LATS1 phosphorylation compared to STAT1 phosphorylation. Consistently, during rhinovirus or influenza virus infection of organotypic HBEC cultures, we observed phosphorylation of both LATS1 and STAT1, but with different kinetics, with LATS1 activation showing earlier resolution compared to STAT1 activation. These results provide a conceptual framework for understanding how IFN receptor signaling differentially controls epithelial functions required for tissue repair and antiviral defense, and inform efforts to target pathological effects of IFNs following viral infection and in other high IFN states.

Interferons (IFNs) initiate antiviral defense when infected cells sense a virus, protecting against infection via JAK/STAT signaling, but can hinder recovery by impairing tissue repair by an unknown mechanism. This study shows that at high concentrations, Type I and III IFN suppress bronchial cell migration and proliferation during tissue repair via JAK-driven LATS1 activation independent of STAT1, separating repair inhibition from antiviral defense.