{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPI16 is emerging as an important regulator in the vascular system. Under conditions of high endothelial shear stress, several PI16 splice variants increase in expression in human coronary artery endothelial cells, where PI16 is present in the endothelium and a subset of vascular smooth muscle cells. In this context, PI16 plays a protective role against atherosclerosis by inhibiting migratory behavior and suppressing secreted matrix metalloproteinase activity, including direct inhibition of MMP2 via binding to a peptide loop above its active site. This anti‐proteolytic function may, however, be lost in inflammatory settings where cytokines such as TNFα and IL‑1β downregulate its expression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n\nIn the realm of adaptive immunity, PI16 marks a distinct subset of CD4+ regulatory T cells (Tregs) that exhibit a memory phenotype. These PI16-positive Tregs express higher levels of FOXP3 and chemokine receptors (e.g., CCR4 and CCR6) and show enhanced migratory capacity toward inflammatory chemokines, suggesting that they are well equipped to traffic to sites of inflammation where they can modulate immune responses. Moreover, detailed analyses in type 1 diabetes patients indicate that these PI16+ Tregs may lose FOXP3 expression at an accelerated rate with disease progression, thereby compromising their regulatory function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n\nPI16 is also implicated in the biology of CD8+ T cells, particularly those programmed for skin homing. In patients with acute graft versus host disease, PI16 is robustly expressed on a subset of skin-homing memory-like CD8+ T cells and is localized to the plasma membrane via a GPI anchor. Here, PI16 appears to regulate local protease activity by inhibiting cathepsin K, thereby potentially modulating the proteolytic microenvironment of the skin."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n\nIn the context of autoimmune pathology, PI16 is upregulated in rheumatoid arthritis, where its overexpression in the synovial tissue and peripheral blood is associated with worsened disease severity. Mechanistically, PI16 interacts with and stabilizes the protein Bmi‑1 in Tregs by blocking its K48‑linked polyubiquitination, which in turn enhances repressive histone modifications at the FOXP3 promoter. This suppression of FOXP3 expression in Tregs contributes to the impaired immune tolerance observed in rheumatoid arthritis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n\nAdditionally, PI16 demonstrates pro-tumorigenic properties in pancreatic ductal adenocarcinoma (PDAC). Elevated PI16 levels in PDAC tissues, relative to adjacent non-tumorous tissues, correlate with disease progression and poor prognosis. Experimental evidence shows that PI16 promotes cellular proliferation both in vitro and in vivo, partly through its binding to oligoadenylate synthetase L (OASL). This interaction suggests that PI16 may drive tumor growth by modulating downstream signaling pathways involved in cell proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Georgina G J Hazell, Alasdair M G Peachey, Jack E Teasdale, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PI16 is a shear stress and inflammation-regulated inhibitor of MMP2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep39553"}], "href": "https://doi.org/10.1038/srep39553"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27996045"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27996045"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Ian C Nicholson, Christos Mavrangelos, Daniel R G Bird, et al. "}, {"type": "b", "children": [{"type": "t", "text": "PI16 is expressed by a subset of human memory Treg with enhanced migration to CCL17 and CCL20."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Immunol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellimm.2012.04.002"}], "href": "https://doi.org/10.1016/j.cellimm.2012.04.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22533972"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22533972"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Christoper M Hope, John Welch, Arunesh Mohandas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Peptidase inhibitor 16 identifies a human regulatory T-cell subset with reduced FOXP3 expression over the first year of recent onset type 1 diabetes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Immunol (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/eji.201948094"}], "href": "https://doi.org/10.1002/eji.201948094"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31127857"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31127857"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Nikolett Lupsa, Barbara Érsek, Andor Horváth, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Skin-homing CD8"}, {"type": "a", "children": [{"type": "t", "text": "sup"}], "href": "sup"}, {"type": "t", "text": "+"}, {"type": "a", "children": [{"type": "t", "text": "/sup"}], "href": "/sup"}, {"type": "t", "text": " T cells preferentially express GPI-anchored peptidase inhibitor 16, an inhibitor of cathepsin K."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Immunol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/eji.201847552"}], "href": "https://doi.org/10.1002/eji.201847552"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30365157"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30365157"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Fang Wang, Xin Gu, Shiyu Lin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Peptidase inhibitor 16 promotes inflammatory arthritis by suppressing Foxp3 expression via regulating K48-linked ubiquitin degradation Bmi-1 in regulatory T cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Immunol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.clim.2023.109883"}], "href": "https://doi.org/10.1016/j.clim.2023.109883"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38147957"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38147957"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Qun Chen, Lu-Yang Jiang, Cheng Cao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Peptidase inhibitor 16 promotes proliferation of pancreatic ductal adenocarcinoma cells through OASL signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Carcinog (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/mc.23699"}], "href": "https://doi.org/10.1002/mc.23699"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38353288"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38353288"}]}]}]}