9.B.312.  The Cytokine Expression and Secretion Mediator and V-type ATPase Regulator, TMEM9 (TMEM9) Family

Human transmembrane protein 9 (TMEM9) is a protein of 183 amino acids with 2 TMSs, one N-terminal, and one about 2/3rds of the way from the N-terminus. The N-terminal region contains several important domains. Homologues are found in animals such as Caenorhabditis elegans and Drosophila melanogaster. In humans, the gene is expressed in many tissues and cells. TMEM9 may play a role in intracellular transport. Wei et al. 2018 studied the expression of the TMEM9 gene and its effect on cytokine secretion in tumor necrosis factor-alpha (TNF-α)-induced LX-2 cells. They showed that overexpression increased the expression of IL-6 and IL-1β. while knockdown decreased their secretion; this enhanced the expression levels of the canonical Wnt/β-catenin genes, accompanied by increased wnt2b, wnt3a and β-catenin protein levels treated with TNF-α. Thus, TMEM9 plays a role in the modulation  of TNF-α-enhanced cytokine (IL-6 and IL-1β) secretion. The canonical Wnt/β-catenin signaling pathway is involved in the induction of the expression of the relevant gene (Wei et al. 2018).  TMEM9 binds to and facilitates assembly of the vacuolar-ATPase (v-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking (Jung et al. 2018).

TMEM9 is a vesicular acidification regulator, and it is highly upregulated in colorectal cancer. TMEM9 binds to and facilitates assembly of the vacuolar-ATPase (V-ATPase), a vacuolar proton pump, resulting in enhanced vesicular acidification and trafficking (Jung et al. 2018). TMEM9-V-ATPase hyperactivates Wnt/β-catenin signalling via lysosomal degradation of adenomatous polyposis coli (APC) (Jung et al. 2021). Moreover, TMEM9 transactivated by beta-catenin functions as a positive feedback regulator of Wnt signalling in colorectal cancer. TMEM9 Is a Wnt signaling amplifier and facilitates V-ATPase assembly for vesicular acidification and lysosomal protein degradation. TMEM9 is highly expressed in regenerating liver and hepatocellular carcinoma (HCC) cells, and expression is enriched in the hepatocytes around the central vein and is also acutely induced by injury. In mice, Tmem9 knockout impairs hepatic regeneration with aberrantly increased adenomatosis polyposis coli (Apc) and reduced Wnt signaling. Mechanistically, TMEM9 down-regulates APC through lysosomal protein degradation through V-ATPase. In HCC, TMEM9 is overexpressed and necessary to maintain β-catenin hyperactivation. TMEM9-up-regulated APC binds to and inhibits nuclear translocation of β-catenin, independently of HCC-associated beta-catenin mutations. Pharmacological blockade of TMEM9-v-ATPase or lysosomal degradation suppresses Wnt/beta-catenin through APC stabilization and beta-catenin cytosolic retention. Thus, our results reveal that TMEM9 hyperactivates Wnt signaling for liver regeneration and tumorigenesis through lysosomal degradation of APC (Jung et al. 2021).

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