{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSphingosine‐1‐phosphate lyase (SGPL1) is the key enzyme that catalyzes the irreversible degradation of sphingosine‐1‐phosphate (S1P), a bioactive lipid that governs the “sphingolipid rheostat” and thereby balances pro‐survival and pro‐apoptotic signals. By reducing S1P levels and modulating downstream ceramide generation, SGPL1 regulates fundamental cell‐fate decisions under stress conditions, influences DNA repair mechanisms and checkpoint recovery, and shapes innate immune responses. These activities have been demonstrated in models where SGPL1 overexpression enhances apoptosis in response to stress and DNA damage while its enzymatic function is critical for proper control of S1P concentrations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant expression or mislocalization of SGPL1 significantly impacts cancer cell behavior. In various malignancies—including colon, oral, prostate, and pediatric rhabdomyosarcoma—altered SGPL1 expression is linked to reduced apoptosis, enhanced cell migration/invasion, resistance to chemo‐ and radiotherapy, and a dedifferentiated state. In some tumor settings, decreased SGPL1 levels are associated with accumulation of S1P, activation of oncogenic signaling pathways (for example, via STAT3), and modulation of receptor recycling, while in other contexts, mutant or mislocalized SGPL1 promotes tumor aggressiveness. Transcriptional regulators such as Sp1 (and its cofactor GATA‐4) and RNA‐binding proteins like hnRNP H1 further modulate SGPL1 expression in cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic alterations disrupting SGPL1 function are now recognized as the cause of a multisystemic syndrome. Recessive mutations that reduce or abolish SGPL1 activity have been implicated in steroid‐resistant nephrotic syndrome accompanied by adrenal insufficiency, ichthyosis, immunodeficiency, and neurological defects. In renal podocytes, SGPL1 deficiency impairs the expression of critical slit diaphragm proteins such as nephrin via dysregulated kinase activity, thereby compromising the glomerular filtration barrier. Such mutations and loss‐of-function alleles highlight the pivotal role of SGPL1 in maintaining sphingolipid homeostasis and normal organ function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these roles in cell survival, SGPL1 modulation influences host defense and neurodegenerative processes. Enhanced SGPL1 activity has been shown to promote type I interferon responses and restrict viral replication, notably reducing influenza virus propagation via activation of JAK/STAT pathways. Similarly, in models of Huntington’s disease, dysregulation of S1P metabolism—and therapeutic inhibition of SGPL1—has been linked to altered histone deacetylase activity, suggesting that controlling SGPL1 function may have neuroprotective benefits in conditions of chronic neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ulrike Reiss, Babak Oskouian, Jianhui Zhou, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0600050103"}], "href": "https://doi.org/10.1073/pnas.0600050103"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17090686"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17090686"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Peter Vogel, Michael S Donoviel, Robert Read, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Incomplete inhibition of sphingosine 1-phosphate lyase modulates immune system function yet prevents early lethality and non-lymphoid lesions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0004112"}], "href": "https://doi.org/10.1371/journal.pone.0004112"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19119317"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19119317"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Young-Jin Seo, Celeste Blake, Stephen Alexander, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sphingosine 1-phosphate-metabolizing enzymes control influenza virus propagation and viral cytopathogenicity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Virol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/JVI.00510-10"}], "href": "https://doi.org/10.1128/JVI.00510-10"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20519401"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20519401"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Evgeny V Berdyshev, Irina Gorshkova, Peter Usatyuk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Intracellular S1P generation is essential for S1P-induced motility of human lung endothelial cells: role of sphingosine kinase 1 and S1P lyase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0016571"}], "href": "https://doi.org/10.1371/journal.pone.0016571"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21304987"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21304987"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "A Kumar, B Oskouian, H Fyrst, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S1P lyase regulates DNA damage responses through a novel sphingolipid feedback mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cddis.2011.3"}], "href": "https://doi.org/10.1038/cddis.2011.3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21368890"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21368890"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Johnatan Ceccom, Najat Loukh, Valérie Lauwers-Cances, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Neuropathol Commun (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/2051-5960-2-12"}], "href": "https://doi.org/10.1186/2051-5960-2-12"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24468113"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24468113"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Emilie Degagné, Ashok Pandurangan, Padmavathi Bandhuvula, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Aberrant expression of the S1P regulating enzymes, SPHK1 and SGPL1, contributes to a migratory phenotype in OSCC mediated through S1PR2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/srep25650"}], "href": "https://doi.org/10.1038/srep25650"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27160553"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27160553"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Weiwei Yang, Anning Wang, Chunling Zhao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "miR-125b Enhances IL-8 Production in Early-Onset Severe Preeclampsia by Targeting Sphingosine-1-Phosphate Lyase 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0166940"}], "href": "https://doi.org/10.1371/journal.pone.0166940"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27935985"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27935985"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Anja Schwiebs, Dominique Thomas, Burkhard Kleuser, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "SGPL1 Deficiency: A Rare Cause of Primary Adrenal Insufficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Endocrinol Metab (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/jc.2018-02238"}], "href": "https://doi.org/10.1210/jc.2018-02238"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30517686"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30517686"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Anna Adamus, Nadja Engel, Guido Seitz "}, {"type": "b", "children": [{"type": "t", "text": "SGPL1"}, {"type": "a", "children": [{"type": "t", "text": "sub"}], "href": "sub"}, {"type": "t", "text": "321"}, {"type": "a", "children": [{"type": "t", "text": "/sub"}], "href": "/sub"}, {"type": "t", "text": " mutation: one main trigger for invasiveness of pediatric alveolar rhabdomyosarcoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Gene Ther (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41417-019-0132-8"}], "href": "https://doi.org/10.1038/s41417-019-0132-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31455837"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31455837"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Keitaro Takahashi, Mikihiro Fujiya, Hiroaki Konishi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterogenous Nuclear Ribonucleoprotein H1 Promotes Colorectal Cancer Progression through the Stabilization of mRNA of Sphingosine-1-Phosphate Lyase 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms21124514"}], "href": "https://doi.org/10.3390/ijms21124514"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32630435"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32630435"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Wajiha Farha Faqar-Uz-Zaman, Katrin G Schmidt, Dominique Thomas, et al. "}, {"type": "b", "children": [{"type": "t", "text": "S1P Lyase siRNA Dampens Malignancy of DLD-1 Colorectal Cancer Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lipids (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/lipd.12282"}], "href": "https://doi.org/10.1002/lipd.12282"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32971566"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32971566"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Saem Mul Park, Catherine E Angel, Julie D McIntosh, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sphingosine-1-phosphate lyase is expressed by CD68+ cells on the parenchymal side of marginal reticular cells in human lymph nodes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Immunol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/eji.201344158"}], "href": "https://doi.org/10.1002/eji.201344158"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24825162"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24825162"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Svjetlana Lovric, Sara Goncalves, Heon Yung Gee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI89626"}], "href": "https://doi.org/10.1172/JCI89626"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28165339"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28165339"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Rathi Prasad, Irene Hadjidemetriou, Avinaash Maharaj, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI90171"}], "href": "https://doi.org/10.1172/JCI90171"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28165343"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28165343"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Tugba Tastemel Ozturk, Nur Canpolat, Seha Saygili, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A rare cause of nephrotic syndrome-sphingosine-1-phosphate lyase (SGPL1) deficiency: 6 cases and a review of the literature."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pediatr Nephrol (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00467-022-05656-5"}], "href": "https://doi.org/10.1007/s00467-022-05656-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35748945"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35748945"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Faik Imeri, Bisera Stepanovska Tanturovska, Roxana Manaila, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss of S1P Lyase Expression in Human Podocytes Causes a Reduction in Nephrin Expression That Involves PKCδ Activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms24043267"}], "href": "https://doi.org/10.3390/ijms24043267"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36834691"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36834691"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Madhuvanthi Vijayan, Chuan Xia, Yul Eum Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sphingosine 1-Phosphate Lyase Enhances the Activation of IKKε To Promote Type I IFN-Mediated Innate Immune Responses to Influenza A Virus Infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1601959"}], "href": "https://doi.org/10.4049/jimmunol.1601959"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28600291"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28600291"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Alba Di Pardo, Enrico Amico, Abdul Basit, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-017-05709-y"}], "href": "https://doi.org/10.1038/s41598-017-05709-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28706199"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28706199"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Leila Pirhaji, Pamela Milani, Simona Dalin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identifying therapeutic targets by combining transcriptional data with ordinal clinical measurements."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-017-00353-6"}], "href": "https://doi.org/10.1038/s41467-017-00353-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28931805"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28931805"}]}]}]}