Dataset Information

DUBbing Down Translation: The Functional Interaction of Deubiquitinases with the Translational Machinery.

ABSTRACT: Cancer cells revamp the regulatory processes that control translation to induce tumor-specific translational programs that can adapt to a hostile microenvironment as well as withstand anticancer therapeutics. Translational initiation has been established as a common downstream effector of numerous deregulated signaling pathways that together culminate in prooncogenic expression. Other mechanisms, including ribosomal stalling and stress granule assembly, also appear to be rewired in the malignant phenotype. Therefore, better understanding of the underlying perturbations driving oncogenic translation in the transformed state will provide innovative therapeutic opportunities. This review highlights deubiquitinating enzymes that are activated/dysregulated in hematologic malignancies, thereby altering the translational output and contributing to tumorigenesis.

SUBMITTER: Kapadia BB

PROVIDER: S-EPMC6727985 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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DUBbing Down Translation: The Functional Interaction of Deubiquitinases with the Translational Machinery.

Kapadia Bandish B BB Gartenhaus Ronald B RB

Molecular cancer therapeutics 20190901 9

Cancer cells revamp the regulatory processes that control translation to induce tumor-specific translational programs that can adapt to a hostile microenvironment as well as withstand anticancer therapeutics. Translational initiation has been established as a common downstream effector of numerous deregulated signaling pathways that together culminate in prooncogenic expression. Other mechanisms, including ribosomal stalling and stress granule assembly, also appear to be rewired in the malignant ...[more]

PMID: 31481479

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Project description:UnlabelledViruses require the host translational apparatus to synthesize viral proteins. Host stress response mechanisms that suppress translation, therefore, represent a significant obstacle that viruses must overcome. Here, we report a strategy whereby the mammalian orthoreoviruses compartmentalize the translational machinery within virus-induced inclusions known as viral factories (VF). VF are the sites of reovirus replication and assembly but were thought not to contain ribosomes. It was assumed viral mRNAs exited the VF to undergo translation by the cellular machinery, and proteins reentered the factory to participate in assembly. Here, we used ribopuromycylation to visualize active translation in infected cells. These studies revealed that active translation occurs within VF and that ribosomal subunits and proteins required for translation initiation, elongation, termination, and recycling localize to the factory. Interestingly, we observed components of the 43S preinitiation complex (PIC) concentrating primarily at factory margins, suggesting a spatial and/or dynamic organization of translation within the VF. Similarly, the viral single-stranded RNA binding protein ?NS localized to the factory margins and had a tubulovesicular staining pattern that extended a short distance from the margins of the factories and colocalized with endoplasmic reticulum (ER) markers. Consistent with these colocalization studies, ?NS was found to associate with both eukaryotic translation initiation factor 3 subunit A (eIF3A) and the ribosomal subunit pS6R. Together, these findings indicate that ?NS functions to recruit 43S PIC machinery to the primary site of viral translation within the viral factory. Pathogen-mediated compartmentalization of the translational apparatus provides a novel mechanism by which viruses might avoid host translational suppression.ImportanceViruses lack biosynthetic capabilities and depend upon the host for protein synthesis. This dependence requires viruses to evolve mechanisms to coerce the host translational machinery into synthesizing viral proteins in the face of ongoing cellular stress responses that suppress global protein synthesis. Reoviruses replicate and assemble within cytoplasmic inclusions called viral factories. However, synthesis of viral proteins was thought to occur in the cytosol. To identify the site(s) of viral translation, we undertook a microscopy-based approach using ribopuromycylation to detect active translation. Here, we report that active translation occurs within viral factories and that translational factors are compartmentalized within factories. Furthermore, we find that the reovirus nonstructural protein ?NS associates with 43S preinitiation complexes at the factory margins, suggesting a role for ?NS in translation. Together, virus-induced compartmentalization of the host translational machinery represents a strategy for viruses to spatiotemporally couple viral protein synthesis with viral replication and assembly.

Dataset Information

DUBbing Down Translation: The Functional Interaction of Deubiquitinases with the Translational Machinery.

Publications

DUBbing Down Translation: The Functional Interaction of Deubiquitinases with the Translational Machinery.

Similar Datasets

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