Abstract
Loss-of-function (LOF) variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are linked to human diseases with high risk of sudden death, including developmental and epileptic encephalopathy and cardiac arrhythmia. β1 Subunits modulate the cell-surface localization, gating, and kinetics of sodium channel pore-forming α subunits. They also participate in cell-cell and cell-matrix adhesion, resulting in intracellular signal transduction, promotion of cell migration, calcium handling, and regulation of cell morphology. Here, we investigated regulated intramembrane proteolysis (RIP) of β1 by BACE1 and γ-secretase and show that β1 subunits are substrates for sequential RIP by BACE1 and γ-secretase, resulting in the generation of a soluble intracellular domain (ICD) that is translocated to the nucleus. Using RNA sequencing, we identified a subset of genes that are downregulated by β1-ICD overexpression in heterologous cells but upregulated in Scn1b-null cardiac tissue, which lacks β1-ICD signaling, suggesting that the β1-ICD may normally function as a molecular brake on gene transcription in vivo. We propose that human disease variants resulting in SCN1B LOF cause transcriptional dysregulation that contributes to altered excitability. Moreover, these results provide important insights into the mechanism of SCN1B-linked channelopathies, adding RIP-excitation coupling to the multifunctionality of sodium channel β1 subunits.
Highlights
Loss-of-function (LOF) variants in SCN1B, encoding (VGSC) β1 subunits, are linked to human diseases that carry a high risk of sudden death, including developmental and epileptic encephalopathy type 52 (DEE52, OMIM 617350), Brugada syndrome 5 (OMIM #612838), and atrial fibrillation, familial, 13 (OMIM #615377). β1 Subunits are type 1 transmembrane proteins containing a single extracellular V-type Ig domain, making them part of the Ig superfamily of cell adhesion molecules (CAMs) [1, 2]. β1 Subunits are multifunctional proteins
We proposed that the β1-intracellular domain (ICD) may participate in transcriptional regulation in vivo and that the absence of β1 regulated intramembrane proteolysis (RIP) and downstream signaling may contribute to disease mechanisms in patients with LOF SCN1B variants
We found the gene groups that were downregulated by β1-ICD overexpression in heterologous cells were upregulated in the Scn1b-null cardiac ventricle, suggesting that the β1-ICD may normally act as a molecular brake on gene expression in heart
Summary
Loss-of-function (LOF) variants in SCN1B, encoding (VGSC) β1 subunits, are linked to human diseases that carry a high risk of sudden death, including developmental and epileptic encephalopathy type 52 (DEE52, OMIM 617350), Brugada syndrome 5 (OMIM #612838), and atrial fibrillation, familial, 13 (OMIM #615377). β1 Subunits are type 1 transmembrane proteins containing a single extracellular V-type Ig domain, making them part of the Ig superfamily of cell adhesion molecules (CAMs) [1, 2]. β1 Subunits are multifunctional proteins. In addition to their canonical roles in modulating the cell-surface localization, gating, and kinetics of sodium channel pore-forming α subunits [3, 4], β1 subunits modulate potassium currents and participate in cell-cell and cell-matrix adhesion as CAMs [5,6,7,8]. Previous work by others showed that β1 subunits undergo regulated intramembrane proteolysis (RIP) through sequential cleavage by the β-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) and γ-secretase [19]. Initial cleavage by BACE1 sheds the β1 extracellular Ig domain, which our laboratory previously showed functions as a ligand for cell adhesion, and leaves the β1-C-terminal fragment (β1-CTF) in the membrane [20, 21]. Cleavage by BACE1 was reported to be the rate-limiting step in β1 RIP. γ-Secretase subsequently cleaves the remaining β1-CTF in the lumen of the membrane, generating a soluble intracellular domain (β1-ICD) (Figure 1B) [19]
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