TM4SF5-mediated CD44v8-10 splicing variant promotes survival of type II alveolar epithelial cells during idiopathic pulmonary fibrosis

Abstract

Reactive oxygen species (ROS) regulate cell fate, although signaling molecules that regulate ROS hormesis remain unclear. Here we show that transmembrane 4 L six family member 5 (TM4SF5) in lung epithelial cells induced the alternatively spliced CD44v8-10 variant via an inverse ZEB2/epithelial splicing regulatory proteins (ESRPs) linkage. TM4SF5 formed complexes with the cystine/glutamate antiporter system via TM4SF5- and CD44v8-10-dependent CD98hc plasma-membrane enrichment. Dynamic TM4SF5 binding to CD98hc required CD44v8-10 under ROS-generating inflammatory conditions. TM4SF5 and CD44v8-10 upregulated cystine/glutamate antiporter activity and intracellular glutathione levels, leading to ROS modulation for cell survival. Tm4sf5-null mice exhibited attenuated bleomycin-induced pulmonary fibrosis with lower CD44v8-10 and ESRPs levels than wild-type mice. Primary mouse alveolar epithelial cells (AECs) revealed type II AECs (AECII), but not type I, to adapt the TM4SF5-mediated characteristics, suggesting TM4SF5-mediated AECII survival following AECI injury during idiopathic pulmonary fibrosis (IPF). Thus, the TM4SF5-mediated CD44v8-10 splice variant could be targeted against IPF.

Crosstalk between TM4SF5 and GLUT8 regulates fructose metabolism in hepatic steatosis

“…TM4SF5 plays regulatory roles in the intracellular trafficking of other membrane proteins and receptors [ 32 ]; it binds to different membrane proteins and receptors, changing their intracellular locations between lysosomal and PMs, presumably leading to changes in signaling activity [ 20 , 22 ]. TM4SF5 binds to EGFR [ 30 ], integrin α5 [ 30 , 33 ], CD133 [ 34 ], CD151 [ 35 ], CD44 [ 36 ], CD98hc/SLC7A11 [ 37 ], SLC27A2/SLC27A5 [ 38 ], and mTOR [ 28 ]. Similarly, TM4SF5 may cause GLUT8 to be trafficked to the PM from lysosomes, where TM4SF5 and GLUT8 are localized separately presumably to transport extracellular fructose.…”

TM4SF5-dependent crosstalk between hepatocytes and macrophages to reprogram the inflammatory environment

“…At the T 5 ERMs for the TM4SF5-enriched microdomain, TM4SF5 can modulate localization, stability, expression, and signaling activity of its binding partners. One such complex forms with a cystine/glutamate antiporter, the xc À system consisting of CD98hc and xCT (SLC7A11), in response to reactive oxygen species (ROS)-generating stimuli for hormetic ROS modulation on lung epithelial cells (Kim et al, 2019). TM4SF5 also binds mTOR, SLC38A9 (an arginine transporter on lysosomal membranes), and L-arginine, playing roles in sensing physiological L-arginine in lysosomes for S6K1 activation and in pooling of cytosolic L-arginine during cell proliferation associated with HCC (Jung et al, 2019).…”

TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

“…PPARa signaling is upregulated in iWAT of cold-exposed mice (43). Furthermore, the PPARa agonist WY-14,643 has been shown to be effective in reducing WAT and BAT adiposity and suppressed inflammation in an HFD-induced mouse model (44). Since PPARa was investigated as a target for the activation of lipid catabolism to improve blood lipid profiles, TM4SF5 KO-induced PPARa signaling could be developed into a therapeutic target for clinical application.…”