Kim, Ji Eon Kim, Hye-Jin Jung, Jae Woo Song, Dae-Geun Park, Dasomi Lee, Haesong Um, Hyejin Park, Jinsoo Nam, Seo Hee Cho, Moonjae Lee, Jung Weon 2024-01-19T19:04:31Z 2024-01-19T19:04:31Z 2021-09-04 2019-09-09 2041-4889 https://pubs.kist.re.kr/handle/201004/119578 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. English NATURE PUBLISHING GROUP MESENCHYMAL TRANSITION CANCER-CELLS TM4SF5 CD44 RESISTANCE REPAIR TM4SF5-mediated CD44v8-10 splicing variant promotes survival of type II alveolar epithelial cells during idiopathic pulmonary fibrosis Article 10.1038/s41419-019-1878-5 1 CELL DEATH & DISEASE, v.10 CELL DEATH & DISEASE 10 scie scopus 000494969700004 2-s2.0-85071993250 Cell Biology Cell Biology Article MESENCHYMAL TRANSITION CANCER-CELLS TM4SF5 CD44 RESISTANCE REPAIR TM4SF5 CD44 idiopathic pulmonary fibrosis type II alveolar epithelial cell