8.A.171.  The Transmembrane Protein 168 (TMEM168) Family 

TMEM168 mutations reduce cardiomyocyte cell surface expression of Nav1.5 (TC# 1.A.1.10.3) through alphaB-crystallin intracellular dynamics. TMEM168 is in the nuclear membrane. A heterozygous mutation (c.1616G>A, p. R539Q) in TMEM168 was identified in patients with Brugada syndrome. This mutation reduced expression of cardiomyocyte sodium channel Nav1.5 via Nedd4-2 E3 ubiquitin ligase-induced ubiquitination and degradation. Nguyen et al. 2021 found that small heat shock protein alphaB-crystallin, which can bind to Nav1.5 and Nedd4-2 (TC# 8.A.30.1.1) to interfere with the association of both proteins, was recruited from the cell surface to the perinuclear region because of the greater interaction of alphaB-crystallin with the TMEM168 mutant than with wild-type TMEM168. Following knockdown of alphaB-crystallin in HL-1 cardiomyocytes, the interaction of Nav1.5 with Nedd4-2 was increased, despite a reduction of the expression level of Nav1.5. Moreover, alphaB-crystallin-mediated reduction of Nav1.5 expression was rescued in the presence of a proteasome inhibitor MG-132, suggesting that alphaB-crystallin-modulated the ubiquitin-proteasome system for the stability of Nav1.5 expression. Thus, interactions between Nav1.5, Nedd4-2, and alphaB-crystallin plays a role in the regulation of cardiomyocyte cell surface expression of Nav1.5, and the TMEM168 mutant disturbs this balance, resulting in a decrease in Nav1.5 expression (Nguyen et al. 2021).