A109-19 A Phosphorylation-dependent Molecular Switch in the Chi3l1-fam13a-pp2a-β-catenin Axis Determines Divergent Tissue Remodeling in Pulmonary Fibrosis and Emphysema

Rationale Idiopathic pulmonary fibrosis (IPF) and emphysema represent distinct phenotypic outcomes of chronic lung injury and aberrant repair. Although both conditions are driven by repetitive epithelial injury and sustained TGF-β signaling, they exhibit markedly different clinical, radiographic, physiological, and pathological profiles. The mechanisms determining whether epithelial injury leads to fibrotic repair or alveolar destruction remain unclear. Previous studies have identified Family with Sequence Similarity 13 Member A (FAM13A) as a susceptibility gene for emphysema, whose protein product interacts with protein phosphatase 2A (PP2A) to regulate β-catenin signaling. Our group previously demonstrated that Chitinase 3-like 1 (CHI3L1) also binds PP2A. We hypothesized that post-translational phosphorylation of CHI3L1 functions as a molecular switch controlling the PP2A-β-catenin axis and thereby determining divergent tissue repair phenotypes. Methods TGF-β transgenic (Tg) mice on C57BL/6 (fibrosis-dominant) and BALB/c (emphysema-dominant) backgrounds were compared for lung histopathology and expression of CHI3L1, FAM13A, PP2A-B, β-catenin, and CDK1. Co-immunoprecipitation assays were performed in 16HBE cells to assess CHI3L1-PP2A-FAM13A interactions. Site-directed mutagenesis (S230A) and a phospho-Ser230-specific CHI3L1 antibody were generated to examine CDK1-dependent phosphorylation of CHI3L1 in THP-1 cells under cytokine stimulation (IL-4/13, IFN-γ) and CDK inhibition with Flavopiridol. Results TGF-β Tg C57BL/6 mice developed elevated levels of active β-catenin and CDK1, whereas BALB/c mice exhibited reduced active β-catenin and CDK1 with increased FAM13A. CHI3L1 and FAM13A competitively bound the PP2A-B subunit in vitro, reciprocally altering β-catenin phosphorylation (Ser33/37/Thr41). Mutation of CHI3L1 Ser230 (S230A) abrogated PP2A binding and β-catenin activation. Flavopiridol and IFN-γ reduced phospho-S230 CHI3L1, whereas IL-4/13 increased it, linking Type 2 inflammation and CDK1 activity to CHI3L1 phosphorylation. Conclusions CDK1 and the balance between Type 1 and Type 2 inflammation regulate phosphorylation of CHI3L1 at Ser230, which acts as a molecular switch directing the β-catenin pathway toward fibrotic (active CHI3L1) or emphysematous (non-active CHI3L1) remodeling through PP2A-FAM13A interactions. This mechanism provides a unifying framework for divergent lung repair outcomes and identifies phospho-S230 CHI3L1 as a potential biomarker and therapeutic target in fibrotic lung disease.