RESUMO
PDZ (PSD-95/Dlg/ZO-1) domain-containing proteins constitute a large family of scaffolds involved in a wide range of cellular tasks, and mainly studied in polarity functions. Diverse host PDZ proteins can be targeted by viral pathogens which express proteins containing PDZ-binding motifs (PDZbm). Previously, we have identified host PDZ-based interactions with the SARS-CoV-2 E protein (2E) in human monocytes. Here, we deepen the study of these interactions by docking and molecular dynamics analyses to identify the most favorable PDZ-PDZbm interaction of seven host PDZ proteins with the PDZbm of 2E. In addition, we analyzed changes in the expression of three of the PDZ proteins identified as 2E interactors in monocytes (syntenin, ZO-2, and IL-16), in human monocyte-derived macrophages (MΦ) and in dendritic cells (DCs) upon stimulation. Our results suggest that these PDZ proteins may have important functions in professional antigen-presenting cells (APCs), and their targeting by the PDZbm of 2E, a central virulence determinant of SARS-CoV-2, support the hypothesis that such PDZ-dependent interaction in immune cells may constitute a viral evasion mechanism. Inhibitor design based on the PDZbm of 2E in the development of drugs against a variety of diseases is discussed.
RESUMO
Mammalian cells depend on extracellular input for the regulation of growth, proliferation and survival. Cancer cells evade these requirements, and are able to take up nutrients in a cell-autonomous fashion, which allows continuous growth and proliferation. To fulfill the high bioenergetic demands imposed by transformation, tumors must develop alternative mechanisms of energy production. Accordingly, the biochemical signature of cancer cells involves a shift to aerobic glycolysis, also known as the "Warburg effect". This property of cancer cells has resulted of great utility in modern medicine for detection of early tumors by positron-emission scanning. Nonetheless, the underlying mechanisms and contribution of the Warburg effect to the malignant phenotype have remained obscure. Thanks to recent advances in cancer research, we are beginning to understand the link between cancer genetics and the abnormal use of glucose by tumors. A new scenario is thus emerging, in which bioenergetics would contribute to and sustain malignant transformation. These findings are not only important for a better understanding of tumorigenesis; tumor reliance on glycolysis can be exploited in the search for novel, more potent therapeutic approaches to cancer treatment.