{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPPL3 is a member of the intramembrane‐cleaving aspartyl proteases that, like its homologues, possesses a type I signal anchor and a membrane‐embedded catalytic domain oriented to cleave type II transmembrane substrates. Structural analyses show that it shares key topology features with signal peptide peptidase (SPP) and other SPPLs, and experimental studies have confirmed its capacity to mediate proteolysis of bona fide SPP substrates as well as substrates from exogenous sources, acting in a sheddase‐like manner. These findings underscore SPPL3’s conserved proteolytic function and its strategic positioning in the endoplasmic reticulum and at the Golgi–ER interface."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA major function of SPPL3 is the regulation of cellular protein glycosylation. By proteolytically releasing the ectodomains of key glycosyltransferases and glycosidases—including enzymes such as N‐acetylglucosaminyltransferase V—SPPL3 modulates the activity and thus the abundance of these enzymes in the Golgi network. This targeted shedding alters global glycosylation patterns, ranging from N‐glycosylation to the biosynthesis of other glycoconjugates, with its substrate specificity influenced by features within their transmembrane domains."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its enzymatic role in glycoprotein processing, SPPL3 contributes to immune modulation and cell signaling. Loss of SPPL3 activity can lead to an altered glycosphingolipid repertoire that hampers effective HLA class I antigen presentation, thereby impairing immune surveillance. In addition, SPPL3 has been implicated in the regulation of lymphocyte signaling by facilitating the association of key Ca²⁺‐signaling components, and its activity has been linked to oncogenic transformation events through activation of metalloproteinases such as ADAM10. Moreover, SPPL3’s proteolytic action is essential for the proper cell surface presentation of certain GPI‐anchored proteins, which in turn may affect complement regulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Elena Friedmann, Marius K Lemberg, Andreas Weihofen, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenilin homologues SPPL2b and SPPL3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M501645200"}], "href": "https://doi.org/10.1074/jbc.M501645200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15998642"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15998642"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Andrew C Nyborg, Thomas B Ladd, Karen Jansen, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Foamy virus envelope protein is a substrate for signal peptide peptidase-like 3 (SPPL3)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.371369"}], "href": "https://doi.org/10.1074/jbc.M112.371369"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23132852"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23132852"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Matthias Voss, Ulrike Künzel, Fabian Higel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Shedding of glycan-modifying enzymes by signal peptide peptidase-like 3 (SPPL3) regulates cellular N-glycosylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embj.201488375"}], "href": "https://doi.org/10.15252/embj.201488375"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25354954"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25354954"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Peer-Hendrik Kuhn, Matthias Voss, Martina Haug-Kröper, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Secretome analysis identifies novel signal Peptide peptidase-like 3 (Sppl3) substrates and reveals a role of Sppl3 in multiple Golgi glycosylation pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Proteomics (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/mcp.M115.048298"}], "href": "https://doi.org/10.1074/mcp.M115.048298"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25827571"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25827571"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Laura Hobohm, Tomas Koudelka, Fenja H Bahr, et al. "}, {"type": "b", "children": [{"type": "t", "text": "N-terminome analyses underscore the prevalence of SPPL3-mediated intramembrane proteolysis among Golgi-resident enzymes and its role in Golgi enzyme secretion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Mol Life Sci (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00018-022-04163-y"}], "href": "https://doi.org/10.1007/s00018-022-04163-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35279766"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35279766"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Marlieke L M Jongsma, Antonius A de Waard, Matthijs Raaben, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Multiepitope tissue analysis reveals SPPL3-mediated ADAM10 activation as a key step in the transformation of melanocytes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.aai8288"}], "href": "https://doi.org/10.1126/scisignal.aai8288"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28292959"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28292959"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Kohei Kawaguchi, Miki Yamamoto-Hino, Satoshi Goto "}, {"type": "b", "children": [{"type": "t", "text": "SPPL3-dependent downregulation of the synthesis of (neo)lacto-series glycosphingolipid is required for the staining of cell surface CD59."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2021.06.093"}], "href": "https://doi.org/10.1016/j.bbrc.2021.06.093"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34303967"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34303967"}]}]}]}