Ask about this productRelated genes to: TMEM63B Blocking Peptide
- Gene:
- TMEM63B NIH gene
- Name:
- transmembrane protein 63B
- Previous symbol:
- C6orf110
- Synonyms:
- DKFZp434P0531, dJ421H19.2
- Chromosome:
- 6p21.1
- Locus Type:
- gene with protein product
- Date approved:
- 2003-11-25
- Date modifiied:
- 2018-11-19
Related products to: TMEM63B Blocking Peptide
Related articles to: TMEM63B Blocking Peptide
- The placental development requires coordinated trophoblast proliferation and differentiation, processes tightly coupled to cell cycle control. Here, we identify TMEM63B, an osmo/mechano-sensitive ion channel, as a key regulator of trophoblast cell cycle progression and placental development. TMEM63B modulates nucleocytoplasmic transport (NCT) by stabilizing NCT components, which govern the nuclear shuttling of key cell cycle regulators in response to osmo/mechanical cues. Loss of TMEM63B compromises Ran protein expression and Ran-XPO1 complex, impairing the nuclear export of CDKN1A/p21. This disruption leads to defective trophoblast proliferation, placental dysfunction, and ultimately perinatal lethality. Our findings establish TMEM63B as a pivotal osmo/mechano-sensitive molecule that regulates nucleocytoplasmic shuttling, providing new insights into how mechanical cues are integrated into nuclear mechanoresponses and placental development. - Source: PubMed
Publication date: 2026/06/08
Cai MengyaLai RuijiaZheng WanshanHuang JianminCao KunLiu XiangCao BinZhang Yang - Transmembrane protein 63B gene (TMEM63B) encodes a mechanosensitive ion channel expressed in alveolar type II epithelial cells, where it mediates stretch-induced surfactant secretion. While heterozygous gain-of-function variants in TMEM63B have been associated with developmental and epileptic encephalopathy, no human disorder has previously been linked to bi-allelic loss-of-function variants. Here, we report five individuals from four unrelated families with childhood interstitial lung disease and bi-allelic predicted loss-of-function variants in TMEM63B. Affected individuals presented with early-onset respiratory distress, chronic hypoxemia, and diffuse parenchymal lung abnormalities on chest imaging. One individual died in infancy, two underwent bilateral lung transplantation, and two require oxygen supplementation. Lung histopathology showed alveolar simplification and type II pneumocyte hyperplasia with electron-dense cores in lamellar bodies and interstitial fibrotic changes, findings consistent with impaired surfactant homeostasis. Developmental delay was observed in all individuals, with speech and language development more severely affected. One presented with white matter changes, and another had mild global atrophy on brain imaging. None of the individuals had epilepsy. Identified variants included two splice donor variants, two nonsense variants, and one frameshift variant, all of which were absent or extremely rare in population databases and segregated with disease. Functional evaluation of the splice donor and nonsense variants from three families supported a loss-of-function mechanism. The pulmonary phenotype of these individuals closely parallels that of Tmem63b-knockout mice, which exhibit neonatal respiratory failure due to impaired surfactant secretion. Collectively, these findings define an autosomal-recessive TMEM63B-related syndromic surfactant dysfunction disorder and expand the phenotypic spectrum of TMEM63B-associated disease beyond the central nervous system. - Source: PubMed
Publication date: 2026/06/08
Chan Sock HoaiIness Audra NRosenfeld Jill ABekheirnia Mir RezaBurrage Lindsay CChau Matthew Hoi KinHtoo Chaerish Eint Myet ChaeKao Eric CKetkar ShamikaLim Wan WanLuo XiMazlan RifhanMizerik ElizabethMun Kein SeongPatel Kalyani RPotocki LorraineRapp Christina KRoca XavierSaianda AnaIglesias-Serrano IgnacioSiew Everlyn CSim Donald YuhuiSpielberg David RTae Sok-KunTeo Jing XianWarfsmann JulianXia Fan Jamuar Saumya STan Ee ShienGriese MatthiasLim Weng KhongThong Meow-KeongMachol Keren - TMEM63B belongs to the OSCA/TMEM63 family of mechanosensitive ion channels. We recently identified it as a mechanosensitive lipid scramblase activated by changes in membrane physical properties. Cryo-EM analysis revealed that recombinant mouse TMEM63B (mTMEM63B) protein adopts either closed or open conformations depending on the detergent environment, and that the monoclonal antibody YN9303-24 stabilizes the open state; however, the antibody epitope and the mechanism of antibody-dependent conformational regulation remained unclear. Here, using chimeric constructs, C-terminal truncations, and internal deletions, we mapped the YN9303-24 epitope to the intracellular C-terminal tail and identified the AQV motif (residues 773-775) as the core binding determinant. Functional analyses revealed that this C-terminal region is essential for maintaining TMEM63B in an inactive state under resting conditions. Deletion of the adjacent LQD motif (Δ776-778) or substitution of Leu776 with alanine induced strong constitutive lipid scrambling, evidenced by phosphatidylserine externalization and enhanced incorporation of fluorescently labeled phosphatidylcholine, whereas substitutions at Gln777 or Asp778 had minimal effects. Structural analysis positioned the AQVLQD motif adjacent to conserved intracellular helices in the open conformation, with Leu776 located near several hydrophobic residues. Together, these findings identify an autoinhibitory role for the C-terminal tail region in maintaining TMEM63B in an inactive state, suggesting that interactions between this tail and intracellular helices regulate the activity of this mechanosensitive lipid scramblase. - Source: PubMed
Publication date: 2026/06/04
Nishimura MegumiMiyata YugoShiraki YuKuribayashi RisaNomura NorimichiNishizawa TomohiroSegawa Katsumori - Inspiration-induced mechanical stretching serves as the primary driving force for pulmonary surfactant secretion from alveolar epithelial type II (AT2) cells. However, the mechanism by which AT2 cells sense mechanical stimuli remains elusive. Here, we demonstrate that TMEM63B functions as a critical mechanosensor on the plasma membrane of AT2 cells. We find that stretch induces significant currents in AT2 cells. Using Tmem63b mice, we show that TMEM63B is expressed on the plasma membrane of AT2 cells. Deletion of TMEM63B in AT2 cells abolishes the stretch-induced currents and suppresses the secretion of pulmonary surfactant. Activation of TMEM63B causes Ca influx, lamellar body (LB) fusion, and pulmonary surfactant secretion. These processes are markedly impaired upon TMEM63B deletion. In contrast, ATP-induced Ca influx and LB fusion are unaffected by TMEM63B deletion, indicating that TMEM63B plays a specialized role in sensing mechanical stretch in the lungs. Therefore, our study establishes TMEM63B as a key mechanosensor critical for AT2 cell-mediated pulmonary surfactant secretion. - Source: PubMed
Publication date: 2026/04/29
Zhan Shi-YuTeng Xiao-YuWu DanZhu YunfengZhang Tian-ZiGuo Hong-LiTan XiaofengYang GuolinLi Gui-ZhouWang Yue-YingZhong Bi-XianDuan Gui-FangChen FengXu JieShi Yun Stone - Major depressive disorder (MDD) is a highly prevalent and disabling neuropsychiatric condition, its underlying molecular mechanisms remain incompletely understood. This study aimed to systematically characterize proteomic alterations in the prefrontal cortex associated with depression-like behaviors induced by chronic stress. Depression-like behaviors in mice were evaluated using standardized behavioral tests and confirmed by Digital Western blotting. Quantitative proteomic analysis of prefrontal cortex tissues was performed to compare chronic social defeat stress (CSDS) and control groups, identifying differentially expressed proteins (DEPs). These DEPs were subsequently subjected to bioinformatic analyses, including Gene Ontology (GO) enrichment and construction of protein-protein interaction (PPI) networks. Key DEPs were further validated by parallel reaction monitoring (PRM) and Western blotting. We found that CSDS mice displayed robust depression-like phenotypes, including decreased sucrose preference and increased immobility. Western blot analysis confirmed the dysregulation of ER stress markers, proinflammatory factors, and proteins related to synaptic plasticity. Proteomic analysis identified 95 differentially expressed proteins, with GO enrichment revealing predominant associations with gene regulation, mitochondrial, metabolic, and synaptic function. PPI network analysis highlighted hub proteins involved in mitochondrial, endoplasmic reticulum, and synaptic regulation. PRM and Western blot validation confirmed dysregulation in four functional modules: 1) Mitochondrial function (Mrpl17, Mrpl41)；2) Signal transduction (Rigi, Pbrm1, Plppr5, Glyr1)；3) Metabolic regulation(Pmvk, Rpl13a, Ubtd2, Tmem63b)；4) Synaptic plasticity (Kif21b, Klc4, Lama2, Col4a2). Our results demonstrate that chronic stress disrupts prefrontal cortical pathways that govern gene regulation, mitochondrial metabolism, and synaptic function, suggesting their concerted contribution to the pathophysiology of depression. - Source: PubMed
Publication date: 2026/02/27
Zhang YiLi LeiZhang XiaoweiXu JiyiKan WeijingWang TianyiDu Jing