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Structural determinant of BST-2-mediated regulation of breast cancer cell motility: a role for cytoplasmic tail tyrosine residues.

ABSTRACT: There is now irrefutable evidence that overexpression of the innate immunity protein-BST-2, in breast cancer cells is implicated in tumor growth and progression. The cellular mechanisms that control BST-2-mediated effect in tumor progression involve enhancement of cancer cell motility-migration/invasion. However, the distinct structural elements of BST-2 that mediate breast cancer cell motility remain unknown. Here, we used various motility assays and different variants of BST-2 to examine the cellular and structural mechanisms controlling BST-2-mediated cell motility. We show that BST-2 silencing in various cancer cell lines inhibits cell motility. Restoration of BST-2 expression using construct expressing wild type BST-2 rescues cell motility. Mutational analysis identifies the cytoplasmic tail of BST-2 as a novel regulator of cancer cell motility, because cell motility was significantly abrogated by substitution of the BST-2 cytoplasmic tail tyrosine residues to alanine residues. Furthermore, in a spheroid invasion model, BST-2-expressing tumor spheroids are highly invasive inside 3D Matrigel matrices. In this model, the spreading distance of BST-2-expressing spheroids was significantly higher than that of BST-2-suppressed spheroids. Collectively, our data reveal that i) BST-2-expressing breast cancer cells in spheroids are more motile than their BST-2-supressed counterparts; ii) BST-2 cytoplasmic tail regulates non-proteolytic (migration) and proteolytic (invasion) mechanisms of breast cancer cell motility; and iii) replacement of the tyrosine residues at positions 6 and 8 in the cytoplasmic tail of BST-2 with alanine residues inhibits cell motility.

SUBMITTER: Naushad W

PROVIDER: S-EPMC5746378 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Structural determinant of BST-2-mediated regulation of breast cancer cell motility: a role for cytoplasmic tail tyrosine residues.

Naushad Wasifa W Mahauad-Fernandez Wadie D WD Okeoma Chioma M CM

Oncotarget 20171129 66

There is now irrefutable evidence that overexpression of the innate immunity protein-BST-2, in breast cancer cells is implicated in tumor growth and progression. The cellular mechanisms that control BST-2-mediated effect in tumor progression involve enhancement of cancer cell motility-migration/invasion. However, the distinct structural elements of BST-2 that mediate breast cancer cell motility remain unknown. Here, we used various motility assays and different variants of BST-2 to examine the c ...[more]

PMID: 29299143

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Project description:Several mammarenaviruses can cause deadly hemorrhagic fever infections in humans, with limited preventative and therapeutic measures available. Arenavirus cell entry is mediated by the viral glycoprotein (GP) complex, which consists of the stable signal peptide (SSP), the receptor-binding subunit GP1, and the transmembrane subunit GP2. The GP2 cytoplasmic tail (CT) is relatively conserved among arenaviruses and is known to interact with the SSP to regulate GP processing and membrane fusion, but its biological role in the context of an infectious virus has not been fully characterized. Using a Pichinde virus (PICV) GP expression vector and a PICV reverse genetics system, we systematically characterized the functional roles of 12 conserved residues within the GP2 CT in GP processing, trafficking, assembly, and fusion, as well as in viral replication. Except for P478A and K505A R508A, alanine substitutions at conserved residues abolished GP processing and membrane fusion in plasmid-transfected cells. Six invariant H and C residues and W503 are essential for viral replication, as evidenced by the fact that their mutant viruses could not be rescued. Both P480A and R482A mutant viruses were rescued, grew similarly to wild-type (WT) virus, and produced evidently processed GP1 and GP2 subunits in virus-infected cells, despite the fact that the same mutations abolished GP processing and membrane fusion in a plasmid-based protein expression system, illustrating the importance of using an infectious-virus system for analyzing viral glycoprotein function. In summary, our results demonstrate an essential biological role of the GP2 CT in arenavirus replication and suggest it as a potential novel target for developing antivirals and/or attenuated viral vaccine candidates.IMPORTANCE Several arenaviruses, such as Lassa virus (LASV), can cause severe and lethal hemorrhagic fever diseases with high mortality and morbidity, for which no FDA-approved vaccines or therapeutics are available. Viral entry is mediated by the arenavirus GP complex, which consists of the stable signal peptide (SSP), the receptor-binding subunit GP1, and the transmembrane subunit GP2. The cytoplasmic tail (CT) of GP2 is highly conserved among arenaviruses, but its functional role in viral replication is not completely understood. Using a reverse genetics system of a prototypic arenavirus, Pichinde virus (PICV), we show that the GP2 CT contains certain conserved residues that are essential for virus replication, implicating it as a potentially good target for developing antivirals and live-attenuated viral vaccines against deadly arenavirus pathogens.

Dataset Information

Structural determinant of BST-2-mediated regulation of breast cancer cell motility: a role for cytoplasmic tail tyrosine residues.

Publications

Structural determinant of BST-2-mediated regulation of breast cancer cell motility: a role for cytoplasmic tail tyrosine residues.

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