Human APOER2 isoforms have differential cleavage events and synaptic properties
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Published version
Date
2022-05-18
Authors
Beffert, Uwe
Omuro, Keri
Ho, Angela
Scrandis, Lauren
Version
First author draft
OA Version
Citation
U. Beffert, K. Omuro, A. Ho, L. Scrandis. 2022. "Human APOER2 isoforms have differential cleavage events and synaptic properties" The Journal of Neuroscience, Volume 42, Issue 20, pp.4054-4068. https://doi.org/10.1523/JNEUROSCI.1800-21.2022
Abstract
Human APOER2 is a type I transmembrane protein with a large extracellular domain (ECD) and a short cytoplasmic tail. APOER2-ECD contains several ligand binding domains (LBD) that are organized into exons with aligning phase junctions, which allows for in-frame exon cassette splicing events. We have identified 25 human APOER2 isoforms from cerebral cortex using gene-specific APOER2 primers, where the majority are exon-skipping events within the N-terminal LBD regions in comparison to 6 identified in the heart. APOER2 undergoes proteolytic cleavage in response to ligand binding that releases a C-terminal fragment (CTF) and transcriptionally active intracellular domain (ICD). We therefore tested whether the diversity of human brain-specific APOER2 variants affects APOER2 cleavage. We found exclusion of different ligand binding repeats from splicing generated different amounts of CTFs compared to full-length APOER2 (APOER2-FL). Specifically, APOER2 isoforms lacking exons 5-8 (Δex5-8) and lacking exons 4-6 (Δex4-6) generated the highest and lowest amounts of CTF generation respectively in response to APOE peptide compared to APOER2-FL. The differential CTF generation of APOER2 Δex5-8 and Δex4-6 coincides with the proteolytic release of the ICD which mediates transcriptional activation facilitated by the Mint1 adaptor protein. Functionally, we demonstrated loss of mouse Apoer2 decreased miniature event frequency in excitatory synapses suggesting that Apoer2 is required for spontaneous neurotransmitter release in mature neurons. Lentiviral rescue with human APOER2-FL or Δex4-6 isoform in Apoer2 knockout neurons fully restored the miniature event frequency but not Δex5-8 isoform. These results suggest that human APOER2 isoforms have differential cleavage events and synaptic properties.
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