SLAC2B‐dependent microtubule acetylation regulates extracellular matrix‐mediated intracellular TM4SF5 traffic to the plasma membranes

Abstract

Transmembrane 4 L six family member 5 (TM4SF5) translocates intracellularly and promotes cell migration, but how subcellular TM4SF5 traffic is regulated to guide cellular migration is unknown. We investigated the influences of the extracellular environment and intracellular signaling on the TM4SF5 traffic with regard to migration directionality. Cell adhesion to fibronectin (FN) but not poly‐l‐lysine enhanced the traffic velocity and straightness of the TM4SF5WT (but not palmitoylation‐deficient mutant TM4SF5Pal−) toward the leading edges, depending on tubulin acetylation. Acetylated‐microtubules in SLAC2B‐positive cells reached mostly the juxtanuclear regions, but reached‐out toward the leading edges upon SLAC2B suppression. TM4SF5 expression caused SLAC2B not to be localized at the leading edges. TM4SF5 colocalization with HDAC6 depended on paxillin expression. The trimeric complex consisting of TM4SF5, HDAC6, and SLAC2B might, thus, be enriched at the perinuclear cytosols toward the leading edges. More TM4SF5WT translocation to the leading edges was possible when acetylated‐microtubules reached the frontal edges following HDAC6 inhibition by paxillin presumably at new cell‐FN adhesions, leading to persistent cell migration. Collectively, this study revealed that cell‐FN adhesion and microtubule acetylation could control intracellular traffic of TM4SF5 vesicles to the leading edges via coordinated actions of paxillin, SLAC2B, and HDAC6, leading to TM4SF5‐dependent cell migration.

TM4SF5-Mediated Regulation of Hepatocyte Transporters during Metabolic Liver Diseases

“…In addition, TM4SF5 and interacting proteins in T 5 ERMs regulate the metabolic status of lipids in hepatocytes and immune cells by affecting multiple levels of lipid metabolism [ 8 ]. Possibly via post-translational modifications of N-glycosylation or palmitoylation of TM4SF5 at residues N138 and N155 or nine cysteines near to the transmembrane domians, TM4SF5 binders can influence expression, activity, stability, binding, and/or subcellular localization, eventually leading to modulated activity of the signaling molecules and pathways [ 20 , 29 ]. It is likely that associations of TM4SF5 with other membrane proteins via the transmembrane domains and cytosolic loop and tails with cytosolic proteins are possible [ 30 ].…”