PDLIM5 Modulates YAP1 Localisation and Fibrogenic Gene Expression in Hepatic Stellate Cells

Abstract

Hepatic stellate cells (HSCs) are the key cellular drivers of liver fibrosis. During liver injury and chronic inflammation HSCs adopt an activated phenotype and secrete fibrotic extracellular matrix (ECM) components such as collagen 1. Mechanical cues derived from the fibrotic ECM drive and support the activation of HSCs, via mechanisms that involve integrins and the mechano-sensitive transcriptional regulator YAP1. It is not yet well understood how external mechanical cues are translated into a molecular response that alters YAP1 nuclear shuttling. There is evidence that suggests the PDZ and LIM domain protein (PDLIM) 5 can regulate YAP1 shuttling in human epithelial cells. We therefore investigated whether PDLIM5 is expressed in HSCs and contributes to YAP1 associated HSC mechano-activation. PDLIM5 protein was detected in HSCs in fibrotic human and mouse liver. PDLIM5 transcript and protein were expressed by primary human and mouse HSCs and by the immortalised HSC LX-2 cell line. PDLIM5 localised with actin stress fibres suggesting a role in HSC adhesion. Co-immunoprecipitation and proximity ligation in LX-2 cells support an association between PDLIM5 and YAP1. We used pharmacological (paclitaxel) and genetic (siRNA and CRISPRi) approaches to inhibit PDLIM5 in HSCs. Inhibiting PDLIM5 reduced YAP1 nuclear localisation and fibrotic gene (COL1A1, ACTA2) expression in LX-2 cells. Overall, these data support a role for PDLIM5 in regulating YAP1 localisation and fibrogenic gene expression in HSCs.

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BibTeX RIS

BibTeX

@misc{worsley2026pdlim5,
  title = {{PDLIM5 Modulates YAP1 Localisation and Fibrogenic Gene Expression in Hepatic Stellate Cells}},
  author = {K. Worsley and D. Abdelmottaleb and L. Ibrahim and E. F. Jennings and H. Kakinuma and J. M. Makopa and A. Meier and R. Pätzold and L. Birchall and T. R. McKay and V. S. Athwal and E. Jokl and K. R. Piper Hanley and J. D. Humphries and J. Pritchett},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.25.748507},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.25.748507v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - PDLIM5 Modulates YAP1 Localisation and Fibrogenic Gene Expression in Hepatic Stellate Cells
AU  - K. Worsley
AU  - D. Abdelmottaleb
AU  - L. Ibrahim
AU  - E. F. Jennings
AU  - H. Kakinuma
AU  - J. M. Makopa
AU  - A. Meier
AU  - R. Pätzold
AU  - L. Birchall
AU  - T. R. McKay
AU  - V. S. Athwal
AU  - E. Jokl
AU  - K. R. Piper Hanley
AU  - J. D. Humphries
AU  - J. Pritchett
PY  - 2026
DA  - 2026/09/25
PB  - bioRxiv
DO  - 10.64898/2026.09.25.748507
UR  - https://www.biorxiv.org/content/10.64898/2026.09.25.748507v1
AB  - Hepatic stellate cells (HSCs) are the key cellular drivers of liver fibrosis. During liver injury and chronic inflammation HSCs adopt an activated phenotype and secrete fibrotic extracellular matrix (ECM) components such as collagen 1. Mechanical cues derived from the fibrotic ECM drive and support the activation of HSCs, via mechanisms that involve integrins and the mechano-sensitive transcriptional regulator YAP1. It is not yet well understood how external mechanical cues are translated into a molecular response that alters YAP1 nuclear shuttling. There is evidence that suggests the PDZ and LIM domain protein (PDLIM) 5 can regulate YAP1 shuttling in human epithelial cells. We therefore investigated whether PDLIM5 is expressed in HSCs and contributes to YAP1 associated HSC mechano-activation. PDLIM5 protein was detected in HSCs in fibrotic human and mouse liver. PDLIM5 transcript and protein were expressed by primary human and mouse HSCs and by the immortalised HSC LX-2 cell line. PDLIM5 localised with actin stress fibres suggesting a role in HSC adhesion. Co-immunoprecipitation and proximity ligation in LX-2 cells support an association between PDLIM5 and YAP1. We used pharmacological (paclitaxel) and genetic (siRNA and CRISPRi) approaches to inhibit PDLIM5 in HSCs. Inhibiting PDLIM5 reduced YAP1 nuclear localisation and fibrotic gene (COL1A1, ACTA2) expression in LX-2 cells. Overall, these data support a role for PDLIM5 in regulating YAP1 localisation and fibrogenic gene expression in HSCs.
ER  -

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