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).
Transmembrane protein 168, TMEM168, of 697 aas and 13 or 14 TMS in a 4 + 5 or 6 + 3 TMS arrangement. TMEM168 mutations reduce cardiomyocyte cell surface expression of Nav1.5 (TC# 1.A.1.10.3) through alphaB-crystallin intracellular dynamics (see family description).
TMEM168 of Homo sapiens
Uncharacterized TMEM168 homologue of 533 aas and 12 or 13 TMSs in a 4 + 3 + 2 + 2 or 3 + 1 TMS arrangement.
TMEM168 of Paragonimus westermani
Uncharacterized protein of 503 aas and 12 TMSs in a 3 + 5 + 2 + 2 TMS arrangement.
UP of Trichuris trichiura (human whipworm)
Uncharacterized TMEM168 homologue of 1163 aas and ~15 TMSs in a 2 + 2 + 3 + 3 + 3 +2 TMS arrangement.
UP of Brachionus calyciflorus