SAMP1/TMEM201 protects alveolar type 2 cells from DNA damage-associated senescence and restrains pulmonary fibrosis
Year: 2026
Type: preprint
Abstract: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive injury to the alveolar epithelium and senescence of alveolar type 2 (AT2) cells drive persistent myofibroblast activation and extracellular matrix deposition. Inner nuclear membrane (INM) proteins organise nuclear architecture and participate in the DNA damage response, but whether they influence epithelial senescence and fibrogenesis is unknown. Here we identify SAMP1/TMEM201, an INM protein that binds lamin A/C, emerin and LINC-complex components, as a compartment-selective protector of AT2 cells. In the bleomycin model of pulmonary fibrosis, SAMP1 was reduced in AT2 cells but unchanged in lung fibroblasts. AT2 cell-specific deletion of Samp1 (Sftpc-Cre^ERT2^; Samp1^flox/flox^) aggravated fibrosis at day 21, with higher Ashcroft scores and increased pulmonary Tnfa and Acta2 expression, whereas intratracheal delivery of AAV6-CAG-Samp1 before bleomycin attenuated both histological fibrosis and these transcriptional responses. In primary AT2 cells analysed immediately after isolation without in vitro stimulation, SAMP1 loss was accompanied by reduced 53BP1 protein, comparable gammaH2AX levels, and upregulation of the senescence-associated and profibrotic markers p16^INK4a^ and PAI-1. These findings define a SAMP1-AT2 senescence axis that constrains pulmonary fibrogenesis and suggest that preserving INM-dependent genome surveillance in the alveolar epithelium may offer an epithelium-directed therapeutic strategy for IPF. Because DNA damage signalling was assessed only under baseline conditions, the data establish an association with altered DNA damage signalling rather than a definitive defect in lesion repair.
Authors: Leonid A Serebryannyy, David A Ball
Institution: Istituto Superiore di Sanità
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7225655989
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