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Thus, it is not surprising that many pathogens can perturb host sphingolipid homeostasis, often to promote pathogenesis.\n                      <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                      is a common opportunistic pathogen that, among many virulence factors, secretes the dual-functioning hemolytic phospholipase C\/sphingomyelinase, PlcH. PlcH contributes to\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      pathogenesis in several ways, and\n                      <jats:italic toggle=\"yes\">plcH<\/jats:italic>\n                      mutants are defective in nearly every infection model, wherein PlcH has been shown to hydrolyze both phosphatidylcholine and sphingomyelin, resulting in inflammation and rupture of host cell membranes. Here, we demonstrate that PlcH can also hydrolyze sphingosylphosphorylcholine (SPC, also known as lysosphingomyelin), an important host signaling sphingolipid responsible for regulating cellular and tissue responses, such as inflammation and endothelial barrier function. PlcH hydrolyzes sphingomyelin to generate phosphocholine and ceramide, and analogously, we demonstrate here that PlcH hydrolyzes SPC to sphingosine and, putatively, phosphocholine. We provide evidence that SPC induction of PlcH is primarily regulated by the sphingosine-responsive SphR regulator and that resultant sphingosine liberated from SPC induces transcription from the other genes in the SphR regulon. This work introduces another way that\n                      <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                      can alter the host sphingolipidome, potentially a different mechanism to promote pathogenesis. The ability of the hemolytic\n                      <jats:italic toggle=\"yes\">Clostridium perfringens<\/jats:italic>\n                      alpha toxin to also cleave SPC suggests that SPC may be a common substrate for phosphocholine-specific phospholipase C.\n                    <\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>\n                        PlcH is a secreted phospholipase C\/sphingomyelinase that is important for the virulence of\n                        <jats:italic toggle=\"yes\">Pseudomonas aeruginosa<\/jats:italic>\n                        . Here, we show that both\n                        <jats:italic toggle=\"yes\">P. aeruginosa<\/jats:italic>\n                        PlcH and\n                        <jats:italic toggle=\"yes\">Clostridium perfringens<\/jats:italic>\n                        alpha toxin can hydrolyze the signaling phospholipid sphingosylphosphorylcholine (SPC), also called lysosphingomyelin. Thus, SPC should be considered a potential target for such phospholipases during infection, as its resulting hydrolysis can induce sphingosine-sensitive genes.\n                      <\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/spectrum.00972-25","type":"journal-article","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T09:00:56Z","timestamp":1751274056000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":3,"title":["Sphingosylphosphorylcholine is a substrate for the\n                    <i>Pseudomonas aeruginosa<\/i>\n                    phospholipase C\/sphingomyelinase, PlcH"],"prefix":"10.1128","volume":"13","author":[{"given":"Pauline","family":"DiGianivittorio","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont","place":["Burlington, USA"]},{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Cellular, Molecular, and Biomedical Sciences Graduate Program, University of Vermont","place":["Burlington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin","family":"Schutz","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont","place":["Burlington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren A.","family":"Hinkel","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont","place":["Burlington, USA"]},{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Cellular, Molecular, and Biomedical Sciences Graduate Program, University of Vermont","place":["Burlington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5659-749X","authenticated-orcid":true,"given":"Matthew J.","family":"Wargo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/0155zta11","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont","place":["Burlington, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.34.3.1071-1074.1981"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.10380"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.20620"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1139\/m97-077"},{"key":"e_1_3_2_6_2","first-page":"7","article-title":"Pathogenetic factors of Pseudomonas aeruginosa","volume":"29","author":"Bergan T","year":"1981","unstructured":"Bergan T. 1981. 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