title: The Mouse-Specific Splice Variant mRAGE_v4 Encodes a Membrane-Bound RAGE That Is Resistant to Shedding and Does Not Contribute to the Production of Soluble RAGE.
abstract: The receptor for advanced glycation end-products (RAGE) is involved in the onset and progression of several inflammatory diseases. The RAGE primary transcript undergoes numerous alternative splicing (AS) events, some of which are species-specific. Here, we characterize the mouse-specific mRAGE_v4 splice variant, which is conserved in rodents and absent in primates. mRAGE_v4 derives from exon 9 skipping and encodes a receptor (M-RAGE) that lacks 9 amino acids between the transmembrane and the immunoglobulin (Ig) domains. RNA-Seq data confirm that in mouse lung mRAGE_v4 is the most abundant RAGE mRNA isoform after mRAGE, which codes for full-length RAGE (FL-RAGE), while in heart all RAGE variants are almost undetectable. The proteins M-RAGE and FL-RAGE are roughly equally abundant in mouse lung. Contrary to FL-RAGE, M-RAGE is extremely resistant to shedding because it lacks the peptide motif recognized by both ADAM10 and MMP9, and does not contribute significantly to soluble cRAGE formation. Thus, a cassette exon in RAGE corresponds to a specific function of the RAGE protein-the ability to be shed. Given the differences in RAGE AS variants between rodents and humans, caution is due in the interpretation of results obtained in mouse models of RAGE-dependent human pathologies.
authors.affiliation: Experimental Cardio-Oncology and Cardiovascular Aging Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Di Maggio
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Gatti
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Jaron
authors.initials: J
authors.lastname: Liu
authors.affiliation: Experimental Cardio-Oncology and Cardiovascular Aging Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bertolotti
authors.affiliation: Institute for Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Fritz
authors.affiliation: Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy.|Università Vita Salute San Raffaele, Milano, Italy.
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.affiliation: Experimental Cardio-Oncology and Cardiovascular Aging Unit, Centro Cardiologico Monzino-IRCCS, Milan, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Raucci