Virus infection induces different cellular responses in infected cells. These include cellular stress responses like autophagy and unfolded protein response (UPR). Both autophagy and UPR are connected to programed cell death I (apoptosis) in chronic stress conditions to regulate cellular homeostasis via Bcl2 family proteins, CHOP and Beclin-1. In this review article we first briefly discuss arboviruses, influenza virus, and HIV and then describe the concepts of apoptosis, autophagy, and UPR. Finally, we focus upon how apoptosis, autophagy, and UPR are involved in the regulation of cellular responses to arboviruses, influenza virus and HIV infections.
The first human Zika virus (ZIKV) outbreak was reported in Micronesia in 2007, followed by one in Brazil in 2015. Recent studies have reported cases in Europe, Oceania and Latin America. In 2016, ZIKV transmission was also reported in the US and the World Health Organization declared it a Public Health Emergency of International Concern. Because various neurological conditions are associated with ZIKV, such as microcephaly, Guillain-Barré syndrome, and other disorders of both the central and peripheral nervous systems, including encephalopathy, (meningo)encephalitis and myelitis, and because of the lack of reliable patient diagnosis, numerous ongoing studies seek to understand molecular mechanisms underlying ZIKV pathogenesis. Astrocytes are one of the most abundant cells in the CNS. They control axonal guidance, synaptic signaling, neurotransmitter trafficking and maintenance of neurons, and are targeted by ZIKV. In this study, we used a newly developed multiplexed aptamer-based technique (SOMAScan) to examine > 1300 human astrocyte cell proteins. We identified almost 300 astrocyte proteins significantly dysregulated by ZIKV infection that span diverse functions and signaling pathways, including protein translation, synaptic control, cell migration and differentiation.
Class I PI3K enzymes play critical roles in B cell activation by phosphorylating plasma membrane lipids to generate two distinct phosphoinositide (PI) products, PI(3,4,5)P3 and PI(3,4)P2. These PIs each bind distinct but overlapping sets of intracellular proteins that control cell survival, cytoskeletal reorganization, and metabolic activity. The tandem PH domain containing proteins (TAPPs) bind with high specificity to PI(3,4)P2, and their genetic uncoupling from PI(3,4)P2 in TAPP knock in (KI) mice was previously found to cause chronic B cell activation, abnormal germinal centers (GCs), and autoimmunity. In this article, we find that TAPPs provide feedback regulation affecting PI3K signaling and metabolic activation of B cells. Upon activation, TAPP KI B cells show enhanced metabolic activity associated with increased extracellular acidification rate, increased expression of glucose transporter GLUT1, and increased glucose uptake. TAPP KI B cells show markedly increased activation of the PI3K-regulated kinases Akt, GSK3β, and p70-S6K. Conversely, overexpression of the C-terminal TAPP PH domains in B cells can inhibit Akt phosphorylation by a mechanism requiring the TAPP PI(3,4)P2-binding pocket. Inhibition of the PI3K pathway in TAPP KI B cells reduced GLUT1 expression and glucose uptake, whereas inhibition of Akt alone was not sufficient to normalize these responses. TAPP KI GC B cells also show increased GLUT1 and glucose uptake, and treatment with the inhibitor of glycolysis 2-deoxy-D-glucose reduced chronic GC responses and autoantibody production within these mice. Our findings show that TAPP-PI(3,4)P2 interaction controls activation of glycolysis and highlights the significance of this pathway for B cell activation, GC responses, and autoimmunity.
Autophagy is a key cellular process that involves constituent degradation and recycling during cellular development and homeostasis. Autophagy also plays key roles in antimicrobial host defense and numerous pathogenic organisms have developed strategies to take advantage of and/or modulate cellular autophagy. Several pharmacologic compounds, such as BafilomycinA1, an autophagy inducer, and Rapamycin, an autophagy inhibitor, have been used to modulate autophagy, and their effects upon notable autophagy markers, such as LC3 protein lipidation and Sequestosome-1/p62 alterations are well defined. We sought to understand whether such autophagy modulators have a more global effect upon host cells and used a recently developed aptamer-based proteomic platform (SOMAscan®) to examine 1305 U-251 astrocytic cell proteins after the cells were treated with each compound. These analyses, and complementary cytokine array analyses of culture supernatants after drug treatment, revealed substantial perturbations in the U-251 astrocyte cellular proteome. Several proteins, including cathepsins, which have a role in autophagy, were differentially dysregulated by the two drugs as might be expected. Many proteins, not previously known to be involved in autophagy, were significantly dysregulated by the compounds, and several, including lactadherin and granulins, were up-regulated by both drugs. These data indicate that these two compounds, routinely used to help dissect cellular autophagy, have much more profound effects upon cellular proteins.
The PI3K signalling pathway is known to regulate B cell metabolic programming upon activation, but the mechanisms involved are not well understood. Here we find that the PI3K pathway controls reprogramming of hexokinases (HKs), the enzymes that convert glucose into glucose-6-phosphate as a key rate-limiting step of glycolysis and other metabolic pathways. In primary mouse B cells, PI3K pathway inhibition substantially impaired the activation-induced increase in extracellular acidification rates (ECAR), a measure of glycolysis. In contrast, B cells isolated from PI3Kdelta gain-of-function mutant mice exhibit elevated ECAR. We find that B cell activation substantially elevates protein levels of HK2 and HK3 isoforms, but not HK1, in a PI3K-dependant manner. PI3K or mTOR inhibition significantly reduced induction of HK2 and HK3 expression, whereas Akt inhibition did not affect HK isoform expression. In human B lymphoma cells, HK isoforms differ significantly in their degree of mitochondrial localization, with HK1 being mitochondrial, HK3 being cytoplasmic and HK2 present in both mitochondria and cytoplasm. To assess whether HK isoforms have unique non-redundant functions, HK2-deficient B lymphoma cells were generated and were found to exhibit decreased ECAR as well as significant changes in metabolomic profile, despite normal expression and localization of HK1 and HK3. Taken together, our study reveals that PI3K-dependant reprogramming of hexokinase isoforms can impact on B cell glycolysis and other metabolic pathways. Studies in progress are examining the functional importance of HK2 in antibody responses using mice with B cell-specific deletion of this enzyme.
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