Exosomes are microvesicles of endosomal origin that are secreted, and their contents (proteins, lipids, DNA, or microRNAs) can alter the physiological states of recipient cells. We demonstrated that phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a tumor suppressor protein normally localized in the cytoplasm and nucleus, was secreted in exosomes. Secreted PTEN was internalized by recipient cells with resultant functional activity, which resulted in reduced phosphorylation of the serine and threonine kinase Akt and reduced cellular proliferation. PTEN secretion in exosomes required Ndfip1, an adaptor protein for members of the Nedd4 family of E3 ubiquitin ligases. Without Ndfip1, neither Nedd4-1 nor Nedd4-2 promoted the recruitment of PTEN into exosomes. In addition, lysine 13 within PTEN, which is required for its ubiquitination by Nedd4-1, was required for exosomal transport of PTEN. These results implicate Ndfip1 as a molecular regulator of the exosomal export of PTEN, with consequences for non-cell-autonomous PTEN activity. Thus, we suggest that the ability of PTEN to exert phosphatase activity beyond the cell in which it is produced has implications for PTEN function during development, health, and disease.
The regulation of metal ion transport within neurons is critical for normal brain function. Of particular importance is the regulation of redox metals such as iron (Fe), where excess levels can contribute to oxidative stress and protein aggregation, leading to neuronal death. The divalent metal transporter 1 (DMT1) plays a central role in the regulation of Fe as well as other metals; hence, failure of DMT1 regulation is linked to human brain pathology. However, it remains unclear how DMT1 is regulated in the brain. Here, we show that DMT1 is regulated by Ndfip1 (Nedd4 family-interacting protein 1), an adaptor protein that recruits E3 ligases to ubiquitinate target proteins. Using human neurons we show the Ndfip1 is upregulated and binds to DMT1 in response to Fe and cobalt (Co) exposure. This interaction results in the ubiquitination and degradation of DMT1, resulting in reduced metal entry. Induction of Ndfip1 expression protects neurons from metal toxicity, and removal of Ndfip1 by shRNAi results in hypersensitivity to metals. We identify Nedd4 -2 as an E3 ligase recruited by Ndfip1 for the ubiquitination of DMT1 within human neurons. Comparison of brains from Ndfip1 ؊/؊ with Ndfip1 ؉/؉ mice exposed to Fe reveals that Ndfip1 ؊/؊ brains accumulate Fe within neurons. Together, this evidence suggests a critical role for Ndfip1 in regulating metal transport in human neurons.cobalt ͉ iron ͉ Nedd4 -2 ͉ ubiquitin T he brain is a specialized organ that requires metals ions for a number of important cellular processes. As such, the brain contains a relatively high concentration of a number of metals such as Fe, Zn, and Cu (in the order of 0.1-0.5 mM) (1). Importantly, the concentrations of these metals are potentially toxic under stress conditions without the requirement of exogenous uptake through ingestion. It is therefore crucial that the brain has highly efficient homeostatic mechanisms in place to prevent aberrant metal toxicity. Over the last decade, growing evidence suggests that the misregulation of metals within the brain is involved in the neuropathology of a number of disorders, such as Parkinson's and Alzheimer's diseases (2). Metal ions are suggested to have two distinct roles in the pathophysiology of brain disorders. Firstly, redox active metals such as Cu, Fe, Mg, and Co can result in metal-catalyzed protein oxidation that leads to protein damage and denaturation (3). Secondly, metal-protein associations can result in protein aggregation and the formation of insoluble protein bodies (4). In addition to the role metals can play in disease states, it has also now become clear that at times of stress, such as in trauma or stroke, neurons become vulnerable to uncontrolled entry of excess metals (3). It is therefore critical that the brain is able to mount cellular defense mechanisms against sudden surges of metal toxicity.Normal metal uptake occurs via transferrin-bound Fe that is incorporated into cells by an endocytotic process initiated by transferrin receptor 1 (TfR1) (5). Non-protein-bound metals can a...
Introduction HIV prevalence among men who have sex with men (MSM) in Vietnam is increasing, while annual HIV testing uptake has remained consistently low, posing a significant challenge to reaching the 90‐90‐90 goals. Barriers to MSM seeking HIV testing include concerns regarding confidentiality and lack of convenient testing options. Two new HIV testing strategies—HIV lay provider and HIV self‐testing (HIVST)—were piloted alongside intensive social media outreach to increase access to and uptake of HIV testing among MSM not actively engaged in services.MethodsWe measured the proportion of first‐time MSM HIV testers opting for HIV lay or self‐testing, and factors that were associated with first‐time testing, as part of a larger HIV lay and self‐testing study among key populations in Vietnam. We also assessed MSM satisfaction with HIV lay or self‐testing, and testing location and provider preferences. Finally, we calculated linkage to care cascade among MSM that were diagnosed and enrolled in anti‐retroviral therapy (ART) services.ResultsAmong MSM that sought HIV lay and self‐testing, 57.9% (n = 320) and 51.3% (n = 412) were first‐time testers respectively. In the final adjusted models, the odds of being a first‐time tester and opting for HIV lay testing were higher among MSM who were young, had lower levels of income and had never exchanged sex for money; for HIVST, the odds of being a first‐time HIV tester were higher among MSM that had attained lower levels of education. HIV lay and self‐testing resulted in higher detection of new HIV cases (6.8%) compared to conventional HIV testing among key populations (estimated at 1.6% in 2016), while MSM linked to testing through social media interventions presented with even higher HIV‐positivity (11%). Combined, 1655 HIV cases were diagnosed and more than 90% were registered for ART services.ConclusionsOur findings suggest that MSM‐delivered HIV testing and self‐testing, promoted through online or face‐to‐face interactions, offer important additions to MSM HIV testing services in Vietnam, and could significantly contribute to epidemic control by increasing HIV testing among harder‐to‐reach and higher‐risk MSM, effectively enrolling them in ART, and reducing onward transmission.
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