Center for Systems Biology

Using an unbiased druggable-genome siRNA screen, this study identified ADAMTS14 as a regulator of YAP nuclear translocation; single-cell and spatial transcriptomics of IPF patient lungs localized ADAMTS14 to a CTHRC1-high myofibroblast population enriched in fibroblastic foci, and knockdown or knockout of ADAMTS14 in IPF patient-derived lung fibroblasts reduced pro-fibrotic, matrisome, and TGFβ-response gene expression; mechanistically, collagen V was identified as an ADAMTS14 substrate whose impaired processing shifted the COL1:COL5 ratio from about 50:1 to about 20:1, producing an unstable matrix with disorganized focal adhesions and reduced FAK-AKT signaling and force transmission.

Using an unbiased druggable-genome siRNA screen, this study identified ADAMTS14 as a regulator of YAP nuclear translocation; single-cell and spatial transcriptomics of IPF patient lungs localized ADAMTS14 to a CTHRC1-high myofibroblast population enriched in fibroblastic foci, and knockdown or knockout of ADAMTS14 in IPF patient-derived lung fibroblasts reduced pro-fibrotic, matrisome, and TGFβ-response gene expression; mechanistically, collagen V was identified as an ADAMTS14 substrate whose impaired processing shifted the COL1:COL5 ratio from about 50:1 to about 20:1, producing an unstable matrix with disorganized focal adhesions and reduced FAK-AKT signaling and force transmission.