{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThe provided body of work does not report any function for SCARNA3. Instead, these studies collectively focus on the role of the intramembrane protease SPPL2a (and, to a lesser extent, its homologue SPPL2b) in regulated intramembrane proteolysis of type II transmembrane proteins. In several investigations, SPPL2a was shown to be essential for cleaving the N‐terminal fragment of CD74—the invariant chain of the MHC class II complex—in antigen‐presenting cells, a process critical for proper endosomal trafficking, B cell development, and function. Deficiency in SPPL2a results in the accumulation of toxic CD74 fragments that impair B cell receptor signaling (via altered PI3K/Akt activation), reduce BAFF‐R expression, and ultimately lead to severe deficits in humoral immunity and dendritic cell homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies have expanded the importance of SPPL2a-mediated proteolysis beyond classical immune responses. In one report, similar regulatory processing by SPPL2a/b was found to control the cellular levels of substrates such as LOX-1 and certain SNARE proteins—a mechanism that influences MAP kinase signaling and confers protection against atherosclerosis. Moreover, evidence from mouse models indicates that SPPL2a is also required in non-immune tissues; for example, its absence in ameloblasts during tooth development disrupts enamel maturation and mineralization, demonstrating a role in tissue homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurthermore, the analyses underscore that SPPL2a deficiency not only disrupts proteolysis of CD74 but also alters dendritic cell function and cytokine profiles, leading to impaired IFN-γ production and increased susceptibility to mycobacterial infections. Detailed mutagenesis studies have identified key elements within the transmembrane and juxtamembrane domains that facilitate SPPL2a cleavage. Across all the studies detailed here—including work on innate and adaptive immunity, cellular trafficking, and even central nervous system implications—none report any involvement of SCARNA3. Thus, while SPPL2a and its substrates have emerged as pivotal regulators of immune and cellular homeostasis, the function of SCARNA3 remains unaddressed within this collection of abstracts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jörg Behnke, Janna Schneppenheim, Friedrich Koch-Nolte, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Signal-peptide-peptidase-like 2a (SPPL2a) is targeted to lysosomes/late endosomes by a tyrosine motif in its C-terminal tail."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2011.08.043"}], "href": "https://doi.org/10.1016/j.febslet.2011.08.043"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21896273"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21896273"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Daniel R Beisner, Petra Langerak, Albert E Parker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20121072"}], "href": "https://doi.org/10.1084/jem.20121072"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23267013"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23267013"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Janna Schneppenheim, Ralf Dressel, Susann Hüttl, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20121069"}], "href": "https://doi.org/10.1084/jem.20121069"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23267015"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23267015"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hannes Bergmann, Mehmet Yabas, Alanna Short, et al. "}, {"type": "b", "children": [{"type": "t", "text": "B cell survival, surface BCR and BAFFR expression, CD74 metabolism, and CD8- dendritic cells require the intramembrane endopeptidase SPPL2A."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20121076"}], "href": "https://doi.org/10.1084/jem.20121076"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23267016"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23267016"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Antonius L J J Bronckers, Nur Gueneli, Renate Lüllmann-Rauch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The intramembrane protease SPPL2A is critical for tooth enamel formation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Bone Miner Res (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jbmr.1895"}], "href": "https://doi.org/10.1002/jbmr.1895"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23426979"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23426979"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Janna Schneppenheim, Susann Hüttl, Torben Mentrup, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The intramembrane proteases signal Peptide peptidase-like 2a and 2b have distinct functions in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.00038-14"}], "href": "https://doi.org/10.1128/MCB.00038-14"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24492962"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24492962"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Owen A Brady, Xiaolai Zhou, Fenghua Hu "}, {"type": "b", "children": [{"type": "t", "text": "Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M113.515700"}], "href": "https://doi.org/10.1074/jbc.M113.515700"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24872421"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24872421"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Susann Hüttl, Kathrin Kläsener, Michaela Schweizer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1403171"}], "href": "https://doi.org/10.4049/jimmunol.1403171"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26157172"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26157172"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Susann Hüttl, Felix Helfrich, Torben Mentrup, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BCJ20160156"}], "href": "https://doi.org/10.1042/BCJ20160156"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26987812"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26987812"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Xiao-Fei Kong, Ruben Martinez-Barricarte, James Kennedy, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41590-018-0178-z"}], "href": "https://doi.org/10.1038/s41590-018-0178-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30127434"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30127434"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Torben Mentrup, Kosta Theodorou, Florencia Cabrera-Cabrera, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20171438"}], "href": "https://doi.org/10.1084/jem.20171438"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30819724"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30819724"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Ann-Christine Gradtke, Torben Mentrup, Christian H K Lehmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficiency of the Intramembrane Protease SPPL2a Alters Antimycobacterial Cytokine Responses of Dendritic Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.2000151"}], "href": "https://doi.org/10.4049/jimmunol.2000151"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33239420"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33239420"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Moritz Ballin, Wolfram Griep, Mehul Patel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The intramembrane proteases SPPL2a and SPPL2b regulate the homeostasis of selected SNARE proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS J (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/febs.16610"}], "href": "https://doi.org/10.1111/febs.16610"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36047592"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36047592"}]}]}]}