Dataset Information

Furin extracellularly cleaves secreted PTENα/β to generate C-terminal fragment with a tumor-suppressive role.

ABSTRACT: PTENα and PTENβ (PTENα/β), two long translational variants of phosphatase and tensin homolog on chromosome 10 (PTEN), exert distinct roles from canonical PTEN, including promoting carcinogenesis and accelerating immune-resistant cancer progression. However, their roles in carcinogenesis remain greatly unknown. Herein, we report that, after secreting into the extracellular space, PTENα/β proteins are efficiently cleaved into a short N-terminal and a long C-terminal fragment by the proprotein convertase Furin at a polyarginine stretch in their N-terminal extensions. Although secreted PTENα/β and their cleaved fragment cannot enter cells, treatment of the purified C-terminal fragment but not cleavage-resistant mutants of PTENα exerts a tumor-suppressive role in vivo. As a result, overexpression of cleavage-resistant PTENα mutants manifest a tumor-promoting role more profound than that of wild-type PTENα. In line with these, the C-terminal fragment is significantly downregulated in liver cancer tissues compared to paired normal tissues, which is consistent with the downregulated expression of Furin. Collectively, we show that extracellular PTENα/β present opposite effects on carcinogenesis from intracellular PTENα/β, and propose that the tumor-suppressive C-terminal fragment of PTENα/β might be used as exogenous agent to treat cancer.

SUBMITTER: Zhang C

PROVIDER: S-EPMC9170693 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Furin extracellularly cleaves secreted PTENα/β to generate C-terminal fragment with a tumor-suppressive role.

Zhang Cheng C Ma Hong-Ming HM Dong Shuang-Shu SS Zhang Na N He Ping P Ge Meng-Kai MK Xia Li L Yu Jian-Xiu JX Xia Qiang Q Chen Guo-Qiang GQ Shen Shao-Ming SM

Cell death & disease 20220606 6

PTENα and PTENβ (PTENα/β), two long translational variants of phosphatase and tensin homolog on chromosome 10 (PTEN), exert distinct roles from canonical PTEN, including promoting carcinogenesis and accelerating immune-resistant cancer progression. However, their roles in carcinogenesis remain greatly unknown. Herein, we report that, after secreting into the extracellular space, PTENα/β proteins are efficiently cleaved into a short N-terminal and a long C-terminal fragment by the proprotein conv ...[more]

PMID: 35668069

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Project description:The type 3 secretion system (T3SS) is essential for bacterial virulence through delivering effector proteins directly into the host cytosol. Here, we identified an alternative delivery mechanism of virulence factors mediated by the T3SS, which consists of the association of extracellularly secreted proteins from bacteria with the T3SS to gain access to the host cytosol. Both EspC, a protein secreted as an enteropathogenic Escherichia coli (EPEC) autotransporter, and YopH, a protein detected on the surface of Yersinia, require a functional T3SS for host cell internalization; here we provide biophysical and molecular evidence to support the concept of the EspC translocation mechanism, which requires (i) an interaction between EspA and an EspC middle segment, (ii) an EspC translocation motif (21 residues that are shared with the YopH translocation motif), (iii) increases in the association and dissociation rates of EspC mediated by EspA interacting with EspD, and (iv) an interaction of EspC with the EspD/EspB translocon pore. Interestingly, this novel mechanism does not exclude the injection model (i.e., EspF) operating through the T3SS conduit; therefore, T3SS can be functioning as an internal conduit or as an external railway, which can be used to reach the translocator pore, and this mechanism appears to be conserved among different T3SS-dependent pathogens.IMPORTANCE The type 3 secretion system is essential for injection of virulence factors, which are delivered directly into the cytosol of the host cells for usurping and subverting host processes. Recent studies have shown that these effectors proteins indeed travel inside an "injectisome" conduit through a single step of translocation by connecting the bacterium and host cell cytoplasms. However, all findings are not compatible with this model. For example, both YopH, a protein detected on the surface of Yersinia, and EspC, an autotransporter protein secreted by enteropathogenic E. coli, require a functional T3SS for host cell translocation. Both proteins have an intermediate extracellular step before their T3SS-dependent translocation. Here, we show an alternative delivery mechanism for these extracellularly secreted virulence factors that are then incorporated into the T3SS to enter the cells; this novel mechanism coexists with but diverges from the canonical injection model that involves the passage of the protein inside the injectisome.

Dataset Information

Furin extracellularly cleaves secreted PTENα/β to generate C-terminal fragment with a tumor-suppressive role.

Publications

Furin extracellularly cleaves secreted PTENα/β to generate C-terminal fragment with a tumor-suppressive role.

Similar Datasets

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