HIV-1 enhances mTORC1 activity and repositions lysosomes to the periphery by co-opting Rag GTPases.

HIV-1 co-opts several host machinery to generate a permissive environment for viral replication and transmission. In this work we reveal how HIV-1 impacts the host translation and intracellular vesicular trafficking machineries for protein synthesis and to impede the physiological late endosome/lysosome (LEL) trafficking in stressful conditions. First, HIV-1 enhances the activity of the master regulator of protein synthesis, the mammalian target of rapamycin (mTOR).

Identification of the adenovirus E4orf4 protein binding site on the B55α and Cdc55 regulatory subunits of PP2A: Implications for PP2A function, tumor cell killing and viral replication.

Adenovirus E4orf4 protein induces the death of human cancer cells and Saccharomyces cerevisiae. Binding of E4orf4 to the B/B55/Cdc55 regulatory subunit of protein phosphatase 2A (PP2A) is required, and such binding inhibits PP2A(B55) activity leading to dose-dependent cell death. We found that E4orf4 binds across the putative substrate binding groove predicted from the crystal structure of B55α such that the substrate p107 can no longer interact with PP2A(B55α).

The adenovirus E4orf4 protein induces G2/M arrest and cell death by blocking protein phosphatase 2A activity regulated by the B55 subunit.

Human adenovirus E4orf4 protein is toxic in human tumor cells. Its interaction with the B alpha subunit of protein phosphatase 2A (PP2A) is critical for cell killing; however, the effect of E4orf4 binding is not known. B alpha is one of several mammalian B-type regulatory subunits that form PP2A holoenzymes with A and C subunits.

Localization and importance of the adenovirus E4orf4 protein during lytic infection.

The human adenovirus type 5 (Ad5) E4orf4 product has been studied extensively although in most cases as expressed from vectors in the absence of other viral products. Thus, relatively little is known about its role in the context of an adenovirus infection. Although considerable earlier work had indicated that the E4orf4 protein is not essential for replication, a recent study using dl359, an Ad5 mutant believed to produce a nonfunctional E4orf4 protein, suggested that E4orf4 is essential for virus growth in primary small-airway epithelial cells (C.

Nuclear localization of the adenovirus E4orf4 protein is mediated through an arginine-rich motif and correlates with cell death.

The adenovirus E4orf4 protein induces p53-independent death of human cancer cells by a mechanism requiring interactions with the Balpha subunit of protein phosphatase 2A. When expressed alone E4orf4 localizes predominantly in the nucleus, although significant levels are also present in the cytoplasm. While tyrosine phosphorylation of E4orf4 and recruitment of Src have been linked with E4orf4 cytoplasmic cell death functions, little is known about the functions of E4orf4 in the nucleus.

Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein.

In transformed cells, induction of apoptosis by adenovirus type 2 (Ad2) early region 4 ORF 4 (E4orf4) correlates with accumulation of E4orf4 in the cell membrane-cytoskeleton fraction. However, E4orf4 is largely expressed in nuclear regions before the onset of apoptosis. To determine the relative contribution of nuclear E4orf4 versus membrane-associated E4orf4 to cell death signaling, we engineered green fluorescent fusion proteins to target E4orf4 to specific cell compartments.