TY - JOUR
T1 - Mouse RAGE variant 4 is a dominant membrane receptor that does not shed to generate soluble RAGE
AU - Peng, Yunqian
AU - Horwitz, Naftali
AU - Lakatta, Edward G.
AU - Lin, Li
N1 - Funding Information:
This work was supported by the intramural research program of the National Instituteon Aging, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted,modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PY - 2016/9
Y1 - 2016/9
N2 - The receptor for advanced glycation end products (RAGE) is a multi-ligand, immunoglobu-lin-like receptor that has been implicated in aging-associated diseases. Recent studies have demonstrated that both human and murine Ager genes undergo extensive alternative splicing that generates multiple putative transcripts encoding different receptor isoforms. Except for the soluble isoform (esRAGE), the majority of putative RAGE isoforms remain unstudied. Profiling of m urine Ager transcripts showed that variant transcript 4 (mRA-GE-v4), the second most abundant transcript in lungs and multiple other tissues, encodes a receptor that lacks nine residues located within the C2 extracellular section close to the trans-membrane domain. We therefore characterized mRAGEV4 isoreceptor in comparison with the full-length mRAGE (mRAGEFL). Although differing in only nine residues, mRA-GEFL and mRAGEV4 display very different cellular behaviors. While mRAGEFL undergoes constitutive, extensive shedding in the cell to generate sRAGE, mRAGEV4 hardly sheds. In addition, we found that while mRAGEFL can localize to both the plasma membrane and the endosome, mRAGEV4 is exclusively localized to the plasma membrane. These very different cellular localization patterns suggest that, in addition to their roles in sRAGE production, mRAGEFL and mRAGEV4 may play distinct, spatiotemporal roles in signaling and innate immune responses. Compared to mice, humans do not have the v4 transcript. Although hRAGE, like mRAGEFL, also localizes to the plasma membrane and the endosome, its rate of constitutive shedding is significantly lower. These observations provide valuable information regarding RAGE biology, and serve as a reference by which to create mouse models relating to human diseases.
AB - The receptor for advanced glycation end products (RAGE) is a multi-ligand, immunoglobu-lin-like receptor that has been implicated in aging-associated diseases. Recent studies have demonstrated that both human and murine Ager genes undergo extensive alternative splicing that generates multiple putative transcripts encoding different receptor isoforms. Except for the soluble isoform (esRAGE), the majority of putative RAGE isoforms remain unstudied. Profiling of m urine Ager transcripts showed that variant transcript 4 (mRA-GE-v4), the second most abundant transcript in lungs and multiple other tissues, encodes a receptor that lacks nine residues located within the C2 extracellular section close to the trans-membrane domain. We therefore characterized mRAGEV4 isoreceptor in comparison with the full-length mRAGE (mRAGEFL). Although differing in only nine residues, mRA-GEFL and mRAGEV4 display very different cellular behaviors. While mRAGEFL undergoes constitutive, extensive shedding in the cell to generate sRAGE, mRAGEV4 hardly sheds. In addition, we found that while mRAGEFL can localize to both the plasma membrane and the endosome, mRAGEV4 is exclusively localized to the plasma membrane. These very different cellular localization patterns suggest that, in addition to their roles in sRAGE production, mRAGEFL and mRAGEV4 may play distinct, spatiotemporal roles in signaling and innate immune responses. Compared to mice, humans do not have the v4 transcript. Although hRAGE, like mRAGEFL, also localizes to the plasma membrane and the endosome, its rate of constitutive shedding is significantly lower. These observations provide valuable information regarding RAGE biology, and serve as a reference by which to create mouse models relating to human diseases.
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U2 - 10.1371/journal.pone.0153657
DO - 10.1371/journal.pone.0153657
M3 - Article
C2 - 27655067
AN - SCOPUS:84992223539
SN - 1932-6203
VL - 11
JO - PloS one
JF - PloS one
IS - 9
M1 - e0153657
ER -